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World Stem Cell Report 2012

World Stem Cell Report 2012

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Published by Brenda Folk
This is a comprehensive progress report for regenerative medicine in all its aspects; Research & Development; Industry, Commercialization & Collaboration; Policy, Regulation & Ethics; Advocacy & Education, and Around the World, a look at stem cell centers around the globe.
This is a comprehensive progress report for regenerative medicine in all its aspects; Research & Development; Industry, Commercialization & Collaboration; Policy, Regulation & Ethics; Advocacy & Education, and Around the World, a look at stem cell centers around the globe.

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Published by: Brenda Folk on Jun 09, 2013
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World Stem Cell Report

Regen. Med. 7(6 Suppl.) (2012)
ISSN 1746-0751

Closing the translational gap

Envision. Empower. Engage.
Realize the potential. The science embraced. Therapies delivered. Whether your work
is in research, translational medicine, advocacy, finance, regulation or policy, you want to see the promise of stem cell science materialize. Genetics Policy Institute (GPI), with a decade of advocacy behind it, continues to champion research, foster collaborations and promote educational and public initiatives that will enable regenerative medicine efforts to develop and flourish. Through our collective impact, we’ll bring the cures.

Embolden the field. GPI works with leading organizations, companies and individuals to
coalesce and strengthen the advocacy community, remove barriers to progress and develop translational pathways. Along with other non-profits such as the Alliance for Regenerative Medicine, International Translational & Regenerative Medicine Center, Stem Cell Action Coalition – and many academic and governmental institutions – GPI catalyzes a worldwide effort to build support and momentum for the field. GPI produces the World Stem Cell Summit, an international forum for sharing knowledge, addressing challenges and heralding achievement. Authors newsletters. Launches legal and policy briefs. Cultivates media relations. And educates and mobilizes the public. All of which adds a powerful voice to the work that you do.

Connect with us. Because you and your organization care about the vitality and progress of regenerative medicine, you’ll want to join forces with GPI. Let us support your efforts. Contact GPI today: www.genpol.org

Genetics Policy Institute


World Stem Cell Report

Closing the translational gap


1 Welcome to the World Stem Cell Report B Siegel

4 8 12

Research & Development
Research Spotlight

StemCells, Inc.: clinical trials of stem cell therapies for CNS disorders M McGlynn Bioengineered vascular graft with autologous stem cells: first use in the clinic M Olausson

Research Updates
17 26 32 41 Key developments in stem cell therapy in cardiology IH Schulman & JM Hare Stem cells and neurodegenerative diseases: where is it all going? RA Barker Ophthalmologic stem cell transplantation therapies TA Blenkinsop, B Corneo, S Temple & JH Stern From cellular therapies to tissue reprograming and regenerative strategies in the treatment of diabetes C Ricordi, L Inverardi & J Domínguez-Bendala

Expert Focus
50 Convergence of gene and cell therapy A Bersenev & BL Levine Contents continued overleaf...

Regenerative Medicine 7(6 Suppl.) (2012)

USA Oreffo R. USA Scharfmann R. USA Benvenisty N.. Invitrogen Rowley JA. UK Cheng L. USA Miller RH. Cleveland Clinic Foundation. Imperial College London. University of Georgia. Univ. for Regenerative Med. MD. RIKEN. CA. University College London. Spain Surani A. Aberdeen. King’s College London. UK Anversa P.. USA Li R-K. Alberta. Northeastern University. CIRM. King’s College London. Univ. UK Martino G. Tufts University School of Med. USA Brüstle O. MA. UK Yoon Y-S. UK Bauer SR. USA Kemp P. OH. Bristol Heart Institute. NY. San Raffaele Hospital. Cambridge Centre for Brain Repair.Regenerative Medicine Editorial Board The Editorial Board is drawn from the leading forces in regenerative medicine Senior Editor Chris Mason. Lapeyronie Hospital. USA Phillipe Menasché. USA Hayek A. Case School of Medicine Cleveland. CA. Histogen Inc. USA Chuang AT. Genetics Policy Institute Sipp D. Technion. Ben’s Stem Cell News. of Med. UK Associate Editors Robert Lanza. GE Healthcare Medical Diagnostics. USA Jorgensen C. New York Medical College. UK Editorial Advisors Ali R. USA Terzic A. UK Sanberg P. Clifford Chance. USA Barker R. Geron.. OH. Thomas Jefferson University. Genzyme Biosurgery. UT Southwestern Medical Center. UK Kloner R. Tengion. USA Waldman SA. Cytograft. NY. Johns Hopkins Uni. McMaster Univ. Pfizer Global R&D. JP Snyder EY. Columbia University. ACT. IS Bertram T. Toronto General Hospital. USA Knoepfler PS. UK du Moulin GC. UK Rao M. Univ. CA. CA Caulfield T. USF Coll. USA Krtolica A. USA Lako M. USA Polak JM. UK Laurencin C. USA Itskovitz-Eldor J. USA Wilson IA. MIT. USA Madeddu P. Univ. Johns Hopkins University School of Med. USA Dunnett S. USA L’Heureux N. Mayo Clinic. USA Russell AJ.. UK Siegel B. London. USA Andrews PW. CAN Salter B. IS Ilic D. Wake Forest University School of Med. Hebrew University of Jerusalem. Univ. USA Hirschi KK. Good Samaritan Hospital (USC). Harvard. INSERM. CA. of Southern California. University College London. FL. Pfizer.. Univ. GA. Inc. CAN MacKay G. SA De Bari C. USA Allsopp T. NC. SDSU Heart Institute. TX. FR Sharpe P. USA Koliatsos V. University of Nottingham. UK Sussman M. CA. Baylor College of Medicine.. USA West M. The Burnham Institute. Food and Drug Administration. Italy McNeish JD. Intercytex. FR Kaplan B. Organogenesis. California San Francisco. MA. Hôpital Européen Georges Pompidou. Reeve-Irvine Research Center. UK Lawford-Davies J.. Germany Buckler L. CA. McGowan Inst. Juvenile Diabetes Research Found. Lonza Cell Therapy. USA Atala A. CA. USA Lewis A. Newcastle. University of Cambridge. Southampton. McGowan Inst. School of Med.. USA Sachlos E. Wales. FRA Gail K Naughton. USA Young L. MA. USA Genbacev O. USA Trounson A. Cell Therapy Group. for Regenerative Med. UK Stem Cell Bank (NIBSC). USA Lebkowski J. CA.. Andalusian Ctr Mol Biol and Regen Med. USA . StemLifeLine. BioTime. USA Keirstead HS. Sheffield. USA Dandashi F. USA Penn MS.. Univ. UK Garry DJ.. UK Patel A. UK Zupanc G. CA. University of California Davis.. TX. PA . FutureMed Company Ltd. Cardiff. MA. Inc. USA Dalton S. USA Glyn Stacey. CAN Chaudhuri J. UK Itescu S. University of Bath. Univ. USA Soria B. Bonn University. UK Adams G. MN. UCSD Whittier Institute. King’s College.

com/loi/rme Indexing: Medline/Index Medicus. commercialization & collaboration 59 Industry highlights D Ilic Opinions 94 Autologous cell therapies: challenges in US FDA regulation TN McAllister. manufacturing and building industry consensus R Deans Alliances. Journal Citation Reports. EMBASE/Excerpta Medica. Regulation & Ethics Commentaries 78 Regulation.718 (2011) . S Johnson & M Rudnicki UK E Culme-Seymour Sweden O Hovatta Brazil R Mendez-Otero & AC Campos de Carvalho 84 136 140 144 89 All World Stem Cell Report 2012 content is available free from the Future Medicine website at www. Biological Abstracts. T Mayleben & G Van Bokkelen 100 Interviews 64 Researchers and the translational reality K Aboody The Regenerative Medicine Coalition F-R Lauter 105 Perspective Pay-to-participate funding schemes in human cell and tissue clinical studies D Sipp 69 Commentary 71 Collaborations in stem cell science J Thomas 113 Advocacy & Education Interviews 114 117 The making of an advocate A Fernandez The New York Stem Cell Foundation S Solomon Organization Profile 74 The International Translational Regenerative Medicine Center M de Veuve Alexis. Biotechnology Citation Index®. Science Citation Index Expanded. futuremedicine. collaborations and consortia: the International Stem Cell Forum and its role in shaping global governance and policy R Isasi Cell standardization: purity and potency BJ Wagner 125 Around the World Global Updates 126 132 USA KRW Matthews & ML Rowland Canada L Willemse.Contents cont. 57 Industry. K-H Grinnemo & R Jove Commentary 120 Why the stem cell sector must engage with social media L Buckler 77 Policy. D Audley & N L’Heureux Autologous cell therapies: the importance of regulatory oversight M Werner. U Ogbogu. BIOSIS Previews. Chemical Abstracts Impact factor: 3.

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GPI has monitored the field since 2003. facilitate collaborations and accelerate the march to cures. As a peerreviewed publication. new commercial ventures. World Stem Cell Summit When the Genetics Policy Institute (GPI) launched the World Stem Cell Report in 2008. Research & Development. (2012) 7(6 Suppl. Executive Director of Genetics Policy Institute and Founder and Co-chair. in the section relating to Advocacy & Education. Industry. Policy. Med. in the section Around the World . societal context to the expanding stem cell ‘multiverse’.12.. The Summit is produced by the GPI and co-organized with the Interdisciplinary Stem Cell Institute (ISCI) of the University of Miami Miller School of Regen.94 © 2012 Future Medicine Ltd ISSN 1746-0751 1 . we take a country and regional look at stem cell centers around the globe. providing our annual industry review with a focus on business development and clinical trials and translational challenges. USA 3–5 December. facilitate collaborations and accelerate the march to cures. Our 2012 World Stem Cell Report aims to provide ‘actionable intelligence’ to the community as part of our mission to enhance societal support.). Brazil. it was to fill an unmet need.Welcome to the World Stem Cell Report Message from Bernard Siegel. and. Sweden. finally. where we include opinion pieces and commentary relating to the role of the US FDA and others in regulating autologous stem cell treatments and the critical need for cell standardization. “ ” 10. and 9 years later we find ourselves immersed in a ‘Cambrian Explosion’ of diversity of rich new research data. Canada and the UK. Florida. 1–2 Our 2012 World Stem Cell Report aims to provide ‘actionable intelligence’ to the community as part of our mission to enhance societal support. the Report reaches a global audience that includes all the attendees of the 8th Annual World Stem Cell Summit in West Palm Beach. Our 2012 World Stem Cell Report is a supplement to the award-winning Medlineand ISI-listed journal Regenerative Medicine (2011 impact factor: 3. a tool for understanding the global. We explore the nooks and crannies of our burgeoning field by examining trends. Regulation & Ethics . We sought to create a new publication in print and made available digitally that would serve as an accessible benchmark and progress report for the emerging field of regenerative medicine. Founder and Editor-in-Chief. Commercialization & Collaboration. inspiration and unique perspectives delivered by an array of international authorities who are experts in their respective disciplines. we provide the insights of leading advocates. focusing on the USA. World Stem Cell Report. new global collaborations and alliances.7). shining light onto the controversies and offering balance..2217/RME. The Report serves as a roadmap to regenerative medicine in all its aspects. spotlighting several key disease categories.

We believe the Report contributes to the collective mission of these wonderful co-organizing institutions and the goals of those assembled for the Summit.Siegel Medicine. 2 Regen. We must all remember that these powerful technologies discussed in the Report hold the promise of delivering actual cures and thus alleviating so much human suffering. International Translational Regenerative Medicine Center (ITRC) and the Kyoto University Institute for Integrated Cell-Material Sciences (iCeMS). Charlotte Barker and the rest of the Future Medicine team for their indispensable contributions to the Report. Professor Chris Mason. Med. (2012) 7(6 Suppl. Karolinska Institute (home of the Nobel Prize in Physiology or Medicine). Let’s work together to reach our collective goals! Cordially. Elisa Manzotti. This is a mighty quest. a huge lift and an exciting journey.) future science group . Diabetes Research Institute. Senior Editor of Regenerative Medicine . I again thank my esteemed colleagues. Societal context and clarity are weapons in the arsenal targeting disease. The world awaits. Beckman Research Institute at City of Hope.

: clinical trials of stem cell therapies for CNS disorders Martin McGlynn Bioengineered vascular graft with autologous stem cells: first use in the clinic Michael Olausson research Updates Key developments in stem cell therapy in cardiology Ivonne H Schulman & Joshua M Hare Stem cells and neurodegenerative diseases: where is it all going? Roger A Barker Ophthalmologic stem cell transplantation therapies Timothy A Blenkinsop. Inc.2217/RME.). Barbara Corneo. (2011) 6(5 Suppl. Luca Inverardi & Juan Domínguez-Bendala Expert focus Convergence of gene and cell therapy Alexey Bersenev & Bruce L Levine 10. xxx–3 ISSN 1746-0751 3 .XX.ADVOCACY & EDUCATION Article type RESEARCH & DEVELOPMENT research spotlight Interviews StemCells. Sally Temple & Jeffrey H Stern From cellular therapies to tissue reprogramming and regenerative strategies in the treatment of diabetes Camillo Ricordi. Med.XX © 2011 Future Medicine Ltd Regen.

Professor Michael Olausson. None of the patients have suffered any major involved in transplantation related research adverse effects from the surgery or the cells themselves. surgeons aim to correct the problem by replacing the damaged vessel with one from another part of the body. stem cells in this way is really exciting. using their human neural stem cell product. (2012) 7(6 Suppl.12. reported The surgeon who carried out the preliminary data from their spinal cord injury trial in May and again procedure. – Written by Charlotte Barker 4 – Written by Jonathan Wilkinson 10. 230–237 (2012). (NSI-566) regained movement in previously paralyzed limbs. when surgeons at Sahlgrenska University Hospital in Sweden used stem cells to grow a replacement blood vessel for a 10-year-old girl.). without any shown measurable improvements in sensory function (response competition.RESEARCH & DEVELOPMENT RESEARCH & DEVELOPMENT Research Highlights RESEARCH SPOTLIGHT Highlighting some of the year’s the most important advances in regenerative medicine and stem cell research Pioneering surgery uses bioengineered vein produced with patient’s own stem cells 2012 saw a world first. that has happened during all these years. we will see more exciting results in the next The company published research in September 2012 5-10 years than we did in 30 years before. The patient is doing well following to develop in this field during 2012. a condition that can cause serious complications and if not treated can lead to a liver transplant being required. three patients with thoracic spinal cord told Regenerative Medicine “I have been injuries have been treated. the most interesting thing to heat.102 © 2012 Future Medicine Ltd Regen. Kuna VK et al. Lancet 380(9838). two of the three patients have 1975.” showing that rats with spinal cord injury injected You can read more in an interview with with the company’s human spinal cord cells Professor Olausson on page 12. onto which the girl’s bone marrow stem cells were seeded Despite the premature halt of Geron’s trial of hESC-derived cells for and differentiated to form a new blood spinal cord injury late last year. Source: Olausson M. However. Meanwhile. touch). in this case that proved impossible so the team went to their Plan B – a tissue engineered blood vessel using the patient’s own cells. The child developed a blood clot in a major blood vessel to her liver. both basic and clinical research continued vessel. To date. The third patient has remained stable. and moved a step closer to clinical trials in spinal cord injury. While the trial since I first started medical school in is predominantly focused on safety. 4–7 ISSN 1746-0751 .. StemCells.: There’s life after Geron for stem cell treatments in spinal cord injury Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. And in my view this is. A deceased donor vein was stripped of all its cells to produce a scaffold. Inc. the transplant. Patil PB. in September 2012. Med.2217/RME. Inc. Normally. who already have a clinical “I think the use of tissue engineering and trial underway for amylotrophic lateral sclerosis (ALS). Neuralstem.

1016/ S0140-6736(12)60028-2 (2012) (Epub ahead of print). Although this research was performed in an in vitro model. Advances are being made in the cornea as well. It means that we have taken the first step towards being able to use stem cells to treat damaged corneas. Stem Cells. but this is the first time that stem cells have been grown on damaged human corneas. Embryonic stem cell trials for macular degeneration: a preliminary report. we have shown that neural stem cells can do some remarkable things. and effectively preserve vision. Inc have also launched a clinical trial in macular degeneration. The Phase I/II trial was approved by the FDA in January 2012 and the trial launched in June 2012 at Retina Foundation of the Southwest’s (RFSW) Anderson Vision Research Center in Texas. Ellerström C et al . USA). StemCells Inc President & CEO. A topic that has been generating a huge amount of excitement throughout 2012 is stem cell-derived cell therapies to treat vision loss. on page 8. The trial is now treating further patients with a higher dose of cells. The researchers reported that two patients.2011.1755-3768. FrancoCardenas V et al . no negative side effects were observed in the patients. The investigators successfully transplanted hESCs into damaged human corneas in vitro and found that they proliferated and differentiated into corneal epitheliallike cells. which could be transplanted into patients. Acta Ophthalmol.” Read more in the full future science group Exciting developments in stem cell therapies to repair damaged retina I think the use of tissue engineering and stem cells in this way is really exciting. showed improvements in their vision for up to 4  months after receiving the cell therapy. Scientists from the Sahlgrenska Academy at the University of Gothenburg (Sweden) used stem cells to regenerate a damaged cornea in the lab. lead author of the study.” Sources: Hubschman P. explained: “Similar www.futuremedicine. Importantly. Heilwell G. interview. so we are very excited to be moving into clinical trials for AMD. – Written by Jonathan Wilkinson 5 . in this case using purified human neural stem cells. Hardarson T. Transplantation of human embryonic stem cells onto a partially wounded human cornea in vitro. In early 2012 the first trial using cells derived from human embryonic stem cells (hESCs) to treat two forms of blindness showed positive results regarding their safety and tolerability. Hanson C. Charles Hanson. one with Stargardt’s macular dystrophy and the other with dry agerelated macular degeneration. using cells developed by Advanced Cell Technology. the researchers are enthusiastic about what implications these findings may have in ophthalmology. and we will see more exciting results in the next 5–10 years than we did in 30 years before. Lancet doi:10.11 11/j. with no signs of deterioration in their vision. Martin McGlynn told Regenerative Medicine “In a rat model of macular degeneration. doi:10. USA.com “ ” experiments have been carried out on animals. Controlled differentiation of hESCs was used to pro­ duce retinal pigment epithelial cells.02358 (2012) (Epub ahead of print). The study was performed at the Jules Stein Eye Institute at the University of California (CA.

2012. The by researchers at Technion-Israel Institute of Technology in Haifa who successfully reprogrammed skin cells from heart failure patients into healthy cardiomyocytes.” Sources: Perin EC. Med. Eur. While the results are still a long way from any clinical application. is enthusiastic about the potential of the work: “What is new and exciting about our research is that we have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young – the equivalent to the stage of his heart cells when he was just born. the simple measure of ejection fraction – percentage of blood pumped from the left ventricle – was improved by 2. so we are very excited to be moving into clinical trials for AMD. Despite this. Lior Gepstein. Zwi-Dantsis L. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity.1093/eurheartj/ehs096 (2012) (Epub ahead of print). with a 4. JAMA doi:10. Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients. (2012) 7(6 Suppl. Although the study failed to show a significant improvement on identified end points. Another cell type with clinical potential was identified Regen. Not only did the cells fully differentiate into cardiomyocytes from human induced pluripotent stem cell. scientists are exploring a range of stem cell types for cardiac repair. we have shown that neural stem cells can do some remarkable things. especially in younger patients. Huber I.” reported Robert Simari from the Mayo Clinic in Rochester (MN. who coordinated the trial. Heart J. left ventricular function. and perfusion in chronic heart failure: the FOCUS-CCTRN trial. As well as bone marrow-derived adult stem cells. USA) added new data to the question of whether the use of bone marrow-derived stem cells will one day be a suitable treatment for heart failure. – Written by Louise Rishton In a rat model of macular degeneration. leading to interesting insights regarding why certain populations respond better to stem cells. the volume of the left ventricle of the heart at the end of a contraction and maximal oxygen consumption derived through a treadmill test.1001/ jama.7% reported improvement over placebo. “ researchers found that these patients has a larger fraction of CD34 + and CD133 + cells in their stored bone marrow cells. “We found that the bone marrow cells did not have a significant impact on the original end points that we chose.418 (2012) (Epub ahead of print). Habib M et al. and these cells may become a possible target in the hunt for targets to improve the engraftment of stem cells in cardiac conditions. This effect was larger in patients under the population’s average age of 63 years.7% over placebo.Authors A complex picture for bone marrow stem cells in heart disease Results published in the Journal of the American Medical Association and announced at the American College of Cardiology’s 61st Annual Scientific Sessions in Chicago (IL. which involved reversibility of a lack of blood supply to the heart. USA) and chairman of the Cardiovascular Cell Therapy Research Network. they also showed full integration into the existing heart tissue in rats.) ” 6 future science group . Pepine CJ et al. leader of the research group. and effectively preserve vision. doi:10. Willerson JT. a small improvement in ejection fraction was reported.

Source: Chen W. hypothesis by demonstrating that a frog egg developed into a functional cloned tadpole after he had substituted the cell nucleus of the frog’s egg cell with a nucleus from a mature. Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. 10. Rivolta was confident the findings provide potential for the future. although the range of improvement was broad. Jongkamonwiwat N.futuremedicine. J. Over 40 years later. Yamanaka S.” Even with the range of results. Centre for Stem Cell Biology. the researchers induced human embryonic stem cells to differentiate into auditory neurons (otic neural progenitors) and hair cell-like cells (otic epithelial progenitors).org/nobel_ prizes/medicine/laureates/2012/# . in 2006. UK).nobelprize. Yamanaka and colleagues discovered that a combination of four genes could reprogram the mature cells to immaturity. demonstrated that human embryonic stem cellderived cells improved hearing in deaf gerbils. By introducing varying combinations of these genes into mature cells. Morphol. a form of deafness that is caused by damage to the neurons that connect the brain to the sensory hair cells. He was able to prove his revolutionary future science group “ Their findings have allowed scientists a greater understanding of cell reprogramming and disease mechanisms and may even lead to the development of new therapies. Project leader. If the next 40 years hold similar advances in knowledge. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. It was demonstrated that 4 weeks after transplantation. 622–640 (1962). and plans to continue the research to test the long-term effects and safety of the treatment. Embryol. Cell 126(4) 663–676 (2006). there was a 46% average overall improvement in hearing. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Marcelo Rivolta. University of Sheffield. These induced pluripotent stem cells could then develop into a variety of mature cell types. Takahashi K.1038/nature11415 (2012) (Epub ahead of print). while in others recovery was poor. specialized cell of a tadpole. www. – Written by Natasha Leeson Nobel Prize in Physiology or Medicine 2012: Gurdon and Yamanaka John Gurdon (UK) and Shinya Yamanaka (Japan) have received the 2012 Nobel prize in physiology or medicine for the discovery that mature cells can be reprogrammed to become pluripotent. explained: “The responses of the treated animals were substantially better than those untreated. Some subjects did very well. the future of stem cell research will be very exciting! Sources: Gurdon JB. Hear it is: a possible cure for deafness? Scientists from the University of Sheffield (Sheffield. The otic neural progenitors were then transplanted into the animals. Yamanaka was able to expand on this research and demonstrate that intact mature cells could be reprogrammed to pluripotency by a specific set of genes. Exp. Nature doi: 10. In this study. Nobel Prize press release: www. Abbas L et al . The gerbils had experimentally induced auditory neuropathy.Written by Natasha Leeson ” 7 .com Their findings have allowed scientists a greater understanding of cell reprogramming and disease mechanisms… It was Gurdon’s 1962 discovery that the fate of specialized cells can be reversed that first opened the door to this new understanding of cell development.

Abbott Ireland Ltd. talks to Regenerative Medicine about the company’s ongoing clinical trials with their human neural stem cell treatment (HuCNS-SC®).2217/RME. meaning we take cells from brain tissue and put them back into the brain.. and was elected to its Board of Directors on February 6. Unlike an embryonic stem cell. Inc. and we put pancreas cells back into the pancreas. Martin McGlynn has spent several decades as a senior executive in the life sciences industry in Europe. The cells we use are unmodified – we do not genetically alter them. then joined Abbott Labs in 1977 where he held positions as General Manager. we take liver cells and put those back into the liver. We do it this way because we are working with adult stem cells. He began his career in Manufacturing Operations with Becton Dickinson. (2012) 7(6 Suppl. Ireland Ltd. Inc. takes an approach that we call homologous use of stem cells. President & Chief Executive Officer of StemCells.81 © 2012 Future Medicine Ltd Regen.12. which can give rise to every cell type in the body (pluripotent). in January of 2001 as President and Chief Executive Officer. We can grow billions of cells in master cell banks and cryopreserve them ready to make patient products for transplant: these really are stem cells in a bottle. are hard-wired to become the three  main cellular actors of the CNS – neurons. Martin McGlynn currently serves as a member of the Board of the Alliance for Regenerative Medicine and is co-Chairman of its Operations and Governance Committee.RESEARCH & DEVELOPMENT Interview StemCells. “ Q In all the transplants we have done (in thousands of animals and 13 patients). the cell type we are working with for CNS indications. they can be directly transplanted as such and are ISSN 1746-0751 8 10. They are expandable to commercial scale in cell banks. human neural stem cells (HuCNS-SC®). Inc. For example. Martin McGlynn joined StemCells. StemCells. so it is a business model that is focused on product development as opposed to a patient-by-patient service business. Inc.). 2001. we have seen no evidence of tumorigenic activity… ” Tell us a little about the company’s approach to developing adult stem cell treatments. Canada and the USA.: clinical trials of stem cell therapies for CNS disorders Interview with Martin McGlynn Martin McGlynn. These cells are hard-wired to become only cells of the CNS. President and General Manager of Abbott Canada Ltd and Vice President of Abbott International Ltd. adult stem cells are essentially hard-wired to their specific organ system. astrocytes and oligodendrocytes – while maintaining a pool of stem cells for lifelong repair and replacement of these specialized cells of the CNS. 8–11 . Med.

This is a progressive and invariably fatal disease. We transplanted over a billion cells into a human brain. In all the transplants we have done (in thousands of animals and 13 patients). We completed that I study in January 2009. it could be thousands of patients from one donor. It is an amazing cell. when you are developing allogeneic transplant methodologies. It is hard to go beyond that observation because it was not a controlled clinical study. but the cells survive way beyond cessation of the immunosuppression. What made StemCells. the immunosuppression is temporary: we stop the immuno­ suppressant regimen after 9  months because by that time it seems the cells have integrated into the body and the host has accommodated them. and start carrying out the cells’ assigned function. where you take donor tissue and transplant it into a host. allogeneic cells can be expanded into millions of cells. With future science group the allogeneic approach we use. All of these trials are using the same cells – HuCNS-SCs. The benefit of the autologous approach is that the patient recognizes the cells as self. we have seen no evidence of tumorigenic activity. the likelihood that they will be rejected when transplanted back into the donor is very low. but my www. processing it in some way and then putting it back into the patient. These cells take their cues from the host microenvironment and. In the CNS. “ ” 9 . So what happens when you put these cells into a living host? They engraft. whether it is in the brain or spinal cord. Importantly. they will predominately become one or another of the cells. they migrate and then they differentiate into neurons. more than 5 years after treatment. choose to explore an allogeneic rather than autologous approach? Put simply. The Phase  results from the Phase I study were very promising. and in time would reject the donor cells. It is more like a service or medical procedure than a product business model. which you can then use to treat thousands of patients. astrocytes or oligodendrocytes in a site-specific way. depending upon the host organ. the spinal cord and the eye. so the US FDA is increasingly comfortable with the safety profile of these cells being transplanted into humans. we do know from trials we have done. that not only do the cells survive with the immunosuppressant regimen and do so for long periods of time. So the immune system will immediately go about setting up defences. it does amazing things when transplanted into animals. the host immune system will recognize the cells from donor tissue as foreign. whereas an autologous approach involves taking patient tissue. The first clinical trial we did was in a fatal lysosomal storage disease. In the case of allogeneic therapies. Could you give us an overview of the clinical trials that are underway at the company? We are the only company worldwide to my knowledge that has clinical trials underway in all three regions of the CNS – the brain. Of the six transplanted patients. you also have to develop immunosuppressant regimens.Clinical trials of stem cell therapies for CNS disorders believed to be nontumorigenic – they do not give rise to tumors (in vitro or in vivo). and we are now in the business of replicating what we’ve seen in human patients. Batten disease.futuremedicine. and the children being treated were at an advanced stage. three of them are still alive today – two patients in the study are.com The benefit of the autologous approach is that the patient recognizes the cells as self. So unless there is something done to the cells to alter them outside the body. This opens up a very broad spectrum for applications in the clinic. Inc. Therefore. with the aim of using the cells to deliver enzymes that were missing in the brains of these patients. the Batten disease study for example. In a liver patient transplant you transplant one  from one donor. It was the first ever human neural stem cell transplantation.

The Batten disease program did not progress to a Phase  II trial due to a lack of enrolment. the ASIA A population who have no sensory or motor function below the level of injury. The simple reason is that it takes our healthcare system too long to come up with the correct diagnoses for these children. Our study design means that we start off with the worst of the worst-affected patients. disease. What we found after 6 months of trying is that we could not identify a single patient who met the study criteria. showing a very good safety profile. and an exciting development is that two of the patients are reporting improved sensation to light touch below the site of injury. Med. which we are all looking forward to. That means we had to find them much earlier. We reported safety data in May of this year. Our game plan is to initiate clinical trials within 4 years. This was a remarkable observation. Here we are using the same neuronal stem cells to myelinate the host axons that are hypomyelinated. but the expectation in terms of the clinical benefit for the subject is not as high. In a rat model of macular degeneration. It is a very intriguing and controversial observation. the axons die and the patient dies in childhood. What we have shown is that HuCNS-SCs are able to enhance memory in animal models of Alzheimer’s disease. especially because there has been little success clinically using strategies targeting plaques. is there a likelihood that the children might benefit from the procedure? In the case of adults you certainly have to be able to demonstrate that it is reasonably safe. The fourth trial is in age-related macular degeneration. A Phase II trial was approved by the FDA. We have announced top-line results and the detailed results of that study are under review in a peer-reviewed journal. UK. The second study we launched was in Pelizaeus–Merzbacher disease (PMD). We completed the PMD trial in February of this year. Is there a body of evidence that suggests that it is reasonably safe to put these cells into children? And secondly. by which time we should have data from the thoracic spinal cord injury clinical trial. The next trial we initiated was in I/II trial spinal cord injury.McGlynn opinion is that you cannot rule out the possibility that the cells have helped these surviving children. And they do so independent of eradicting plaques and tangles. while the fourth patient was clinically stable. but they are biologically active. but could not be completed due to insufficient enrolment. We plan to be in London. and have started enrolling the ASIA B’s. All four patients undergoing transplantation in that study were shown to have no myelin on their nerve axons at baseline. it is hard to know whether it is caused by the cells or by progression of the injury. good or bad. When the brain’s myelin is damaged or insufficient (hypomyelinated). What new clinical trials do you hope to initiate over the next few years? We recently got a US$20 million award from the California Institute for Regenerative Medicine to initiate INDenabling activities for a trial in cervical spinal cord injuries. The Batten and PMD trials enrolled children with genetic brain disorders. Three of the four patients presented small but measureable improvement in neurological markers. So the purpose of the second study was to go into patients who had most of their neurons intact. These patients have no myelin or very little myelin and are incapable of generating myelin. Is enrolment likely to be problem for the PMD program? In the case of the first study. That is where the majority of spinal cord injuries occur. which was enrolling patients within a couple of weeks of spinal cord injury. the spinal cord and the eye. USA. Not only did the cells engraft and survive. and initiated the study in June 2012 at the Retina Foundation of the Southwest’s Anderson Vision Research Center in TX. This makes 3–12  it very different to the Geron study. (2012) 7(6 Suppl. We had a Phase I/II study authorized by the FDA in January 2012. 10 and if there is an effect. There is a heightened sense of scrutiny with regards to the risk–reward equation. We enroll patients months postinjury. Children future science group We are the only company worldwide to my knowledge that has clinical trials underway in all three regions of the CNS – the brain. In preclinical development is a very important program in Alzheimer’s Regen. so we are very excited to be moving into clinical trials for AMD. in September to present data on the 6-month evaluation of these patients. for which we have again applied for funding of up to US$20 million for IND-enabling activities. a fatal hypo­ myelination disorder. we have shown that neural stem cells can do some remarkable things. which occur a little further up the spine. Are there any special challenges in conducting clinical trials in children? There are elevated regulatory and ethical considerations when you conduct any clinical trials in children. and they appear to have conferred a clinical benefit to these patients. a Phase  being carried out in Switzerland and authorized by Swissmedic.) “ ” . we put the cells into the worst-affected children – most of their neurons had already died so there was very little left to protect with our cells. We have dosed all three ASIA-A patients in the first cohort. who have incomplete injury. closer to the neck. Our view is that if you put cells in too early they may not survive in what is a very hostile inflammatory environment. and effectively preserve vision.

it is not an easy path to biggest the clinic. Inc. and say we have done all the heavy lifting when it comes to the scientific premise. as well as investors. We are in a state of watchful waiting. the California Institute for Regenerative Medicine is like the US cavalry as far as we are concerned: we have been waiting for them to come over the hill! They are certainly going to be a game changer in terms of helping companies like ours make it through the valley of death and come out the other side with human clinical data. Thankfully. PMD is another rare disease but in children with the most severe form. How do you think the field of stem cell therapy will develop over the next 5–10 years? The field is maturing rapidly. connatal PMD. It is always challenging for patients and their families. ­ future science group www. the sponsor of the preclinical and clinical studies described in the manuscript. and the rigor and design of our clinical trials.. press releases and other corporate communications. there is a big question mark over who is going to fund companies engaged in translation through the ‘valley of death’ between proof of principle and the clinic. but until such a time as our healthcare system has addressed the problem and is able to diagnose much earlier. it is obvious from infancy that there is something wrong so these children are diagnosed very early. It takes more than 2 years on average.com 11 . Ultimately. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The venture capital community appears disinterested in the stem cell space and the public investor community is skittish. But often the children are initially misdiagnosed and treated with seizure meds. So we should not have the same problem we had with Batten disease of identifying early-stage patients.futuremedicine. Inc. the parents start to notice their children are not hitting developmental milestones and start to get seizures. So we were forced to shelve the program. However. to cut through all the hype and figure out what is real. No writing assistance was utilized in the production of this manuscript. until such time as we have clinical data proving efficacy. In the case of StemCells. the spinal cord and the eye. I can only speak for StemCells. We are definitely open to re-intiating the trial if that situation does come about. (“Company”). The Company has previously disclosed. …the two biggest challenges facing the industry are being able to separate the good science from the bad and to sustain funding… “ ” Financial & competing interests disclosure M McGlynn is a director and employee of StemCells. not because we were not confident about the technology and the ability to help these kids. in SEC filings. to separate the wheat from the chaff. The rate of progress in opening up clinical trials and advancing towards the clinic has accelerated exponentially. In terms of funding. It is only after the seizure meds do not control the disease that eventually somebody orders the diagnostic tests. the clinical and preclinical information discussed in the manuscript. Inc. in California. It is going to become more and more difficult to discern what is important and what is not. it is going to be a struggle. the preclinical data. sceptical and confused. by which time pathology is too severe and they have lost most of their neurons. Over time. over the next 3–4 years we will have human clinical data and results of clinical trials from the brain. I think the two  challenges facing the industry are being able to separate the good science from the bad and to sustain funding. We even had a 14-month-old baby in our trial.Clinical trials of stem cell therapies for CNS disorders with Batten disease for all intents and purposes look very healthy – there are no immediate tell-tale signs.

ISSN 1746-0751 The actual time to produce it [the vessel] was in the order of 3–5 weeks.99 © 2012 Future Medicine Ltd Regen. Q How did you first become involved in vascular tissue engineering? It started 5 or 6  years ago.12. As it turned out. Your research group has received a lot of media attention recently concerning the implantation of a donor vein that was bioengineered with autologous stem cells to treat a young girl with extrahepatic portal vein obstruction.). Med. not performing in school. such as arteries and veins. Those are the two main fields that we’re currently engaged in.2217/RME. 12–15 . as we would expect with the usual surgery. These methods were plan A but we were concerned that the patient’s own vessels were on the short side. plan A proved problematic. because you have to have a good source for the matrix and then collect the cells and so on. It is really important to get the flow back because sooner or later the patient would be a candidate for a liver transplant.RESEARCH & DEVELOPMENT Interview Bioengineered vascular graft with autologous stem cells: first use in the clinic Interview with Michael Olausson Michael Olausson talks to Regenerative Medicine about the pioneering clinical use of a bioengineered vascular graft to treat a 9-year-old girl with extrahepatic portal vein obstruction and the future potential of bioengineered vessels. and the other on airways. There was an intriguing talk about kidneys in pigs and later I heard about Doris Taylor’s work with tissue engineered hearts. having difficulty in grasping the curriculum and are not reaching the goals that children their age are expected to. What are the key research activities your group is currently engaged in? We have two main projects: one involves the synthesis of vascular blood vessels. What led to this particular patient being selected for the new procedure? The patient was 9 years old at the time of diagnosis. I was at the American Society for Transplant Surgeons winter meeting in the USA. Before the surgery the parents will typically report that the child is tired. Therefore. How long did it taken to produce the implant? The actual time to produce it was in the order of 3–5 weeks. There was uncertainty as to whether the patient was a candidate for traditionally used methods: either using an open umbilical vein or the jugular veins. So it would not be the type of thing that you could use for an emergency procedure. These factors made this patient suitable to try the new technique. to provide a back-up option. and that is a more risky procedure and costs a lot of money. only for elective or planned surgery. (2012) 7(6 Suppl. Those two  lectures fascinated me and really sparked my interest in the field of tissue engineering. we asked for permission to use the bone marrow stem cells from the girl to produce a bioengineered vessel. where some of the lectures dealt with tissue engineering. which is very late for thrombosis of that particular vessel. as compassionate use. “ ” 12 10. What was the outcome of the surgery for the patient? Well it was quite a dramatic change. the bioengineered vessel. so therefore we used our plan B.

which required the patient to have further surgery later on. What are the main benefits & problems with this method compared with existing techniques? The main advantage is that it is almost a self-made product – it is as close as possible to a vein being made by a patient. reviews and book chapters in the field of transplantation. This means that the technique does not need any immunosuppressive drugs. So you have to hope for an open umbilical vein. The downsides would mainly be the logistics of producing future science group bioengineered vessels on an everyday basis. And in my view [the bioengineered vessel] is.futuremedicine. His scientific interests include transplant immunology and experimental and clinical transplantation studies. “ ” 13 .Bioengineered vascular graft with autologous stem cells: first use in the clinic Michael Olausson has been Professor of Transplantation Surgery at Gothenburg University (Gothenburg. and potentially for other kinds of vessels. as far as we know. which may not always be available. The vessel itself is good and it is now 6 months on from the second procedure. and not have to worry about finding a suitable vein in the patient to transplant. he performed the first operation in the world using a stem cell-derived vein and recently he performed the two first mother-to-daughter live donor uterus transplantations in the world. it is challenge but I think it is possible. because it is disadvantageous to take away one of the very important veins for giving fluids. The parents of this patient reported almost immediately that they could see a difference. further operations and experiments will be successful and open up new opportunities. In the past. Last year. they have too low patency. as you would with a transplant from a donor. artificial grafts are not an option. Sweden) between 1994 and June 2011. that she was a lot more active and responded quicker. He has pioneered several innovative surgical procedures in the Nordic countries. In 2008 he received the Carl-Gustav Groth Scandinavian Transplant Prize. the girl was much more awake and active. Sweden) since 2000. and board member and Vice President of the European Liver and Intestinal Transplantation Association. I am sure there will be more patients in the future who will be operated on www. There was a problem. in case of emergency procedures. We are very intrigued by the result and it provides an important proof-of-concept. Especially when you use the existing method of transplanting one of the jugular veins. We also noted a difference when the girl was in the hospital. He has published over 240 original articles. Do you think that the use of bioengineered vessels will one day overtake existing techniques? Yes. but this was not. Especially with this specific operation. so I truly believe that it works. and was Chairman of the Sahlgrenska Transplant Institute at Sahlgrenska University Hospital (Gothenburg. He has been invited as a speaker at several national and international meetings all over the world. the most interesting thing that has happened during all these years. together with a team from Gothenburg. he has been President of The Swedish Transplantation Society. In these cases it would be an advantage to have a tailor-made vessel. Hopefully. the only thing different is the matrix.com I first started medical school in 1975. I think so. Europe and the rest of the world. without any competition. related to the bioengineered vessel. and took part in games and in school work.

and we will see more exciting results in the next 5–10 years than we did in 30 years before.000–80.Olausson using this technique. No writing assistance was utilized in the production of this manuscript. then I am sure it is cost effective. the most interesting thing that has happened during all these years. but of course you have to evaluate the method more carefully on a case-by-case basis.) future science group . grants or patents received or pending. if you compare using the bioengineered vessel with a successful procedure using the patient’s own vessels. If it is a choice between the bioengineered vessel or a liver transplant. If you can show that the bioengineered vessel works. stock ownership or options. honoraria. This includes employment. How does the bioengineered graft compare with standard procedures on cost? Of course it depends on where you start counting. And in my view this is. 14 Regen. At least here in Sweden a liver transplantation costs approximately €70. It is also a procedure that carries a 10% mortality rate within the first year. I think the use of tissue engineering and stem cells in this way is really exciting. (2012) 7(6 Suppl. or even is more efficient. or royalties. How do you expect the field of tissue engineered vascular grafts to develop over the next 5–10 years? I have been involved in transplantationrelated research since I first started medical school in 1975.000 and that is not counting the medications and all the other steps that the patient has to undergo before liver transplantation. expert testimony. this technique would save the health provider a lot of money. consultancies. the bioengineered vessel costs more. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. Med. without any competition. On the other hand.

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University of Miami Miller School of Medicine. Recent therapeutic approaches involve bone marrowderived mononuclear cells and mesenchymal stem cells.12. existing mechanistic studies support the importance of the release Ivonne H Schulman. Interdisciplinary Stem Cell Institute. With regards to MSCs. mesenchymal stem cells (MSCs) [2. Stem cell therapy has emerged as a strategy aimed at preventing or reversing myocardial injury and promoting cardiac tissue regeneration (Figure 1). is the use of cell-based therapy. transendocardial stem cell injection has been established. the cardiovascular stem cell field has rapidly advanced and now numerous adult stem cell sources. Successful cell-based tissue regeneration involves a complex orchestration of cellular and molecular events that include stem cell engraftment and differentiation.3  million Americans and is a leading cause of heart failure as well as cardiovascular mortality. Miami Veterans Affairs Healthcare System. FL. Keywords: cardiac stem cell n cell transplantation n heart failure n ischemic heart disease n mesenchymal stem cell n myocardial infarction Ischemic heart disease affects an estimated 16. Regarding the types of stem cells. legal. However. Over the past half-century. as well as the safety and efficacy of various methods of cell delivery and usefulness and precision of diverse imaging modalities to assess therapeutic efficacy [2–4] .11–16] .: +1 305 243 1999. biological [5] and immunologic [6] issues have hindered their use in human trials. Med.80 © 2012 Future Medicine Ltd Regen. Miami. Preclinical models of ischemic heart disease employing large animals have been instrumental in advancing phenotypic and mechanistic insights underlying stem cell therapy. a process that eventually leads to ventricular dysfunction and arrhythmias. USA. Future studies will focus on determining the most efficacious cell type(s) and/or cell combinations and the mechanisms underlying their therapeutic effects. FL.edu 10.2217/RME. embryonic stem cells (ESCs) can differentiate into all adult cell types and have been shown to have the potential for cardiac regeneration in animal models.).RESEARCH & DEVELOPMENT Research Update Key developments in stem cell therapy in cardiology Ivonne H Schulman & Joshua M Hare* A novel therapeutic strategy to prevent or reverse ventricular remodeling. Tel. Miami. jhare@med. durability and safety of human cell reprogramming and genetic-engineering strategies remain the subject of investigation [9. USA.10] . adipose tissue-derived stem cells. and Nephrology-Hypertension Section. including bone marrow-derived mono­ nuclear cells (BMMNCs) [2. are under clinical evaluation. and proliferation of endogenous cardiac stem cells. cardiac-derived stem cells and cell combinations. However. 17–24 ISSN 1746-0751 17 . advances in risk factor modification and pharmacological and interventional therapeutic approaches have dramatically improved the quality and quantity of life of patients with ischemic heart disease. the safety of catheter-based. These proof-of-concept studies have paved the way for ongoing pivotal trials. adipose tissue-derived stem cells [18] and cardiac-derived stem cells [19. University of Miami Miller School of Medicine. USA *Author for correspondence: Joshua M Hare. Miami. induced-pluripotent stem cells [7] or induced cardiomyocytes [8] . These approaches have only recently started to be investigated clinically and the reproducibility.17] .20] . existing therapeutic strategies do not directly reverse the scar formation or progressive ventricular remodeling that follows a myocardial infarction (MI). as well as stimulation of neovascularization and endogenous cell proliferation. ethical. Fax: +1 305 243 3906. (2012) 7(6 Suppl. Clinical trials employing mesenchymal stem cells and cardiac-derived stem cells have demonstrated efficacy in infarct size reduction and regional wall contractility improvement. FL. It has become evident that the mechanisms underlying the therapeutic strategy of stem cell transplantation involves an orchestration of events including reduction of cardiac cell death and fibrosis. the substrate for heart failure and arrhythmias following a myocardial infarction. Interdisciplinary Stem Cell Institute. secretion of anti-inflammatory and angiogenic mediators. An attractive alternative to ESCs is the programming of adult somatic cells into ESC-like. Nevertheless.miami. accounting for approximately one in six deaths in the USA [1] . Regarding delivery methods.

the sustainability of the left ventricular Recent developments Figure 1. notably. (LV) ejection fraction (LVEF) improvement in the treated group [11] .14] . On the other hand. one ongoing and one  completed. is comparing the safety and efficacy of intracoronary delivery of BMMNCs at 3 and 7 days post-MI in patients with ST-segment elevation [16] . Translational development of novel clinical therapies for heart disease.17] . the LateTIME trial investigated whether delaying BMMNC delivery for 2–3  weeks following MI and primary percutaneous coronary intervention improves global and regional LV function [13. randomized. the Phase II clinical trial ENACT-AMI will investigate the efficacy and safety of autologous EPCs and autologous EPCs transfected with human endo­ thelial nitric oxide synthase (NCT00936819). (2012) 7(6 Suppl. Importantly. as well as for development of newer generations and combinations of stem cell products that have greater efficacy and sustainability (durability) [4.) . patients with acute MI received an intracoronary infusion of ex vivo expanded BMMNCs or culture-enriched endothelial progenitor cells derived from peripheral blood MNCs [11] . controlled. „„ Acute MI Several studies over the past decade have tested intracoronary bone marrow infusions in patients with acute MI (Table 1). Most recently. This evaluation strongly supports the soon-to-start BAMI trial (NCT01569178).Schulman & Hare of trophic. Two clinical trials. Phase  III study that will investigate whether intracoronary infusion of autologous BMMNCs is safe and reduces all-cause mortality in patients with reduced LVEF (EF ≤45%) after successful reperfusion for acute MI. This enhanced understanding of phenotypic response and mechanistic appreciation of the underpinnings of stem cell therapy can be harnessed for improved trial design. No significant changes between baseline future science group Laboratory Cell discovery Mechanistic hypotheses tested Animal Facility Preclinical safety and efficacy studies Therapeutic hypothesis tested Clinic Phase I–III safety and efficacy trials Novel mechanistic and therapeutic hypotheses formulated 18 Regen.10] . Med. This is a multinational. This article reviews the most recent developments in the clinical use of stem cells as a therapeutic strategy for cardiac structural and functional repair in acute and chronic ischemic heart disease. anti-inflammatory and immunomodulatory factors in addition to cell engraftment. The growing human phenotypic data from recent and ongoing clinical trials supports the notion that stem cell therapy is safe and has the capacity for repair of cardiac structure as well as restoration of cardiac function [4. Pharmacologic and genetic  approaches are also under investigation with the aim of enhancing the therapeutic efficacy of cell-based therapy [9. are testing the impact of cell therapy timing on therapeutic potential. this meta-analysis confirmed a long-observed clinical benefit that is out of proportion to increases in cardiac function: BMMNC therapy reduced the incidence of death. differentiation and. The 5-year results demonstrated the long-term safety of intracoronary delivery of autologous BMMNCs in acute MI and. stimulation of endogenous cardiac stem cell (CSC) recruitment and differentiation [21] . For instance. recurrent MI and stent thrombosis in patients with ischemic heart disease.22] . a meta-analysis of 50  studies (2626 patients) confirmed the idea that this strategy prevents remodeling by reducing infarct size and LV chamber enlargement and that these benefits persisted during long-term follow-up [23] . notably. In the TOPCARE-AMI trial. The ongoing Phase II trial developed by the Cardiovascular Cell Therapy Research Network. the TIME study.

as measured by cardiac MRI. NCT00313339). double-blind. Three  dose levels were investigated in cohorts of five  patients each. In a randomized. With regard to other cell types and sources. heart failure and rehospitalization for cardiac complications compared with patients receiving placebo. patients underwent infarct-related artery infusion of autologous bone marrow-derived CD34 + cells after ST elevation MI at a median of 8. Recently published stem cell therapy clinical trials for ischemic heart disease. open-label study. controlled. MSC: Mesenchymal stem cell.futuremedicine. the enormous expansion potential in culture. potential as an allogeneic cell therapeutic. the current evidence supporting the use of MSCs as a cellbased therapeutic for ischemic heart disease include ease of accessibility for isolation. in the BMMNC group compared with placebo.3  days after coronary stenting [24] . double-blind pilot trial evaluating the safety and effect of intracoronary administration of BMMNCs 2–3 weeks following acute myocardial infarction TOPCARE-AMI 5‑year results First randomized study investigating the effects of intracoronary infusion of circulating or bone marrow-derived progenitor cells in patients with successfully reperfused acute myocardial infarction FOCUS-CCTRN Randomized. controlled. placebo-controlled trial evaluating the safety and efficacy of percutaneous delivery with a transendocardial catheter delivery system of autologous bone marrow-derived MSCs or BMMNCs in patients with chronic ischemic cardiomyopathy and heart failure secondary to myocardial infarction SCIPIO (ongoing) Randomized. Osiris Therapeutics. dose-escalation study of the safety and efficacy of intracoronary delivery of cardiospherederived stem cells in patients with ischemic cardiomyopathy and a recent myocardial infarction Year reported (2011) Type of trial Phase II RCT Patients (n) 87 Cell type Ref.) were recently investigated in a Phase II.com 19 .Key developments in stem cell therapy in cardiology and 6-month measures were observed in LVEF and wall motion in the infarct and border zones. RCT: Randomized clinical trial. double-blinded. Table 1. and ethical considerations. Of particular clinical interest is the potential use of allogeneic MSCs. homing and migratory behavior to sites of tissue injury. Inc. placebo-controlled. infarct-related artery infusion of CD34 + cells in patients with acute MI (AMR-01. There is growing evidence that cell dose impacts therapeutic potential. This small. placebo-controlled study investigating the efficacy of transendocardial delivery of BMMNCs in patients with chronic ischemic cardiomyopathy TAC-HFT (ongoing) Randomized. These findings indicate that the 2–3-week post-MI time-point may exceed the therapeutic window of intracoronary BMMNC therapy. future science group www. doseescalation pilot study reported that improved perfusion and infarct size reduction correlated with the quantity and mobility of the infused CD34 + cells. Autologous BMMNCs [13] (2011) Phase I RCT 55 Autologous BMMNCs [11] (2012) Phase II RCT 92 Autologous BMMNCs [15] (2011) Phase I/II RCT 8 Autologous MSCs BMMNCs [2] (2011) Phase I RCT 23 Autologous c-kit+ cardiac stem cells [19] (2012) Phase I RCT 25 Autologous cardiospherederived stem cells [20] BMMNC: Bone marrow-derived mononuclear cell. CD34 + cells are hematopoietic stem cells that have been shown to improve perfusion and function in myocardial and limb ischemia models by stimulating neovascularization directly through endothelial lineage differentiation and indirectly through the secretion of proangiogenic factors. which would preclude the need for the patients’ bone marrow aspiration and the timely culture expansion of their MSCs. immunomodulatory prop­ erties. Trial LateTIME Randomized. placebo-controlled study investigating the safety of intracoronary cardiac stem cell therapy in patients with chronic ischemic cardiomyopathy CADUCEUS Randomized. stressinduced ventricular arrhythmia. It was preliminarily reported by Osiris [Unpublished Data] that a single intravenous infusion of either Prochymal or placebo within 7  days of an acute heart attack significantly reduced cardiac hypertrophy. bone marrowderived allogeneic MSCs (Prochymal®. presumptive plasticity. paracrine-mediated effects. In this regard. 220 patient study in the setting of acute MI with depressed EF.

In addition. reduction in infarct size. The PRECISE trial (NCT00426868). POSEIDON-DCM (NCT01392625). The first study. Madrid. defined as reduction in infarct size at 6 months. reverse remodeling after 12  Importantly. Although the study showed no significant effect on LV end-systolic volume. These findings support the notion that certain 20 bone marrow-derived cell populations may provide a greater regenerative benefit and thereby determine clinical efficacy. such as infarct size and regional contractility. exploratory analyses demonstrated significant improvement in stroke volume and LVEF. doubleblind. Moreover. the APOLLO trial (NCT00442806). The first eight patients (four received MSCs and four received BMMNCs) demonstrated decreased infarct size and improved Regen. Our group has shown in a preclinical large animal model of chronic MI that surgical injection of bone marrowderived autologous as well as allogeneic MSCs results in a reduction in infarct size and an increase in regional myocardial contractility [21. randomized. reported at the 7th International Symposium on Stem Cell Therapy and Cardiovascular Innovation. placebo-controlled trial evaluated the safety and efficacy of percutaneous delivery with a transendocardial catheter delivery system of autologous bone marrow-derived MSCs or BMMNCs in patients with chronic ischemic cardiomyopathy and heart failure secondary to MI. These findings are being translated into improvements in clinical outcomes. which can be directly measured and accurately reflect clinical outcomes. the findings from our preclinical studies as well as this clinical study suggest that the selection of end points. the noncultured adipose stromal vascular fraction. which correlated with higher bone marrow CD34 + and CD133 + progenitor cell counts. a randomized. supporting the conduct of larger-scale studies to verify these beneficial effects in patients with refractory angina. This Phase  I/II. „„ Chronic ischemic cardiomyopathy & heart failure The FOCUS-CCTRN is a Phase  II trial in patients with chronic ischemic cardiomyopathy that investigated the 6-month efficacy of transendocardial delivery of BMMNCs on myocardial function and perfusion [15] . and improvement in myocardial perfusion [25] . This double-blind. ongoing clinical trial. Similarly. showed improvement in LVEF. dilated cardiomyopathy. The results from the first eight patients of the TAC-HFT trial have recently been published [2] . A lipoaspirate is obtained by liposuction under local anesthesia and the adiposederived stem and regenerative cells are isolated using the Celution™ System (Cytori Therapeutics). Phase  II clinical trial to evaluate the safety and efficacy of intramyocardial injections of autologous CD34 + cells in patients with refractory chronic myocardial ischemia on maximal therapy who were not suitable candidates for conventional revascularization [26] . the MyStromalCell trial (NCT01449032). is being tested in two  clinical trials. Cell therapy was associated with significant improvements in angina frequency and exercise tolerance at both 6 and 12 months compared with placebo treatment.28. randomized. The preliminary data. is a double-blind. our group is conducting two clinical trials comparing the safety and efficacy of bone marrow-derived allogeneic and autologous MSCs. placebo-controlled trial evaluating the safety (defined as major adverse cardiac and cerebral events at 6 months) of intracoronary infusion of autologous adipose-derived stem and regenerative cells in acute MI patients after successful revascularization. Med. controlled clinical trial using noncultured adipose stromal vascular fraction cells. a heterogeneous population of cells with multilineage differentiation potential. it was noted that improvements in regional months after function observed at 3  cell therapy predicted the degree of LV months. In this regard. controlled clinical trial in patients with dilated cardiomyopathy reported that intracoronary infusion of CD34 + cells was associated with an increase in LVEF and 6‑min walk distance and a lower secondary end point of 1-year mortality or heart transplantation [27] . there is also preclinical evidence for the therapeutic potential of adipose tissuederived MSCs [18] . but no clinical trials have been initiated yet in acute MI patients. (2012) 7(6 Suppl. which most cell therapy trials have used as the primary efficacy end point [2. a smaller randomized. placebo-controlled trial in patients with chronic ischemic heart disease is investigating the efficacy and safety of intramyocardial delivery of VEGF-A165-stimulated autologous adipose tissue-derived MSCs to improve myocardial perfusion and exercise capacity and reduce symptoms. maximal oxygen consumption or myocardial perfusion.) regional contractility. aims to establish the safety and efficacy of transendocardial autologous versus allogeneic MSC therapy in patients with nonischemic. A Phase II/III trial the ADVANCE study (NCT01216995) has been initiated to further evaluate the efficacy of this approach. tested the effect of intramyocardial delivery in patients future science group . NCT00300053) investigators conducted a double-blind. However. there is only one ongoing clinical trial using culture-expanded adipose tissue-derived MSCs. the first direct randomized head-to-head comparison of autologous versus allogeneic MSCs delivered by transendocardial injection.Schulman & Hare In terms of the source of MSCs.29] .3] . Spain. The initial findings of the POSEIDON study (NCT01087996). could represent more suitable measures of cell therapy efficacy than global LVEF. Currently. will be presented as a late-breaking clinical trial at the American Heart Association Scientific Sessions in November 2012 [30] . in May 2010. A parallel. the ACT34CMI (Adult Autologous CD34 + Stem Cells.

Recently published results from the ongoing Phase I clinical trial. The increase in LVEF was associated with an improvement in regional wall contractility in the infused LV regions as well as all the LV segments combined.5–3 months after MI.10. A preliminary report in a porcine model of MI showed that the combination of MSCs and c-kit+ CSCs is more effective at reducing infarct size and restoring cardiac function than either cell type alone [40] . as well as route and timing of delivery.Key developments in stem cell therapy in cardiology with chronic ischemic cardiomyopathy. The differences in clinical outcomes may be related to variability in study design. „„ Combination cell therapy Based on our findings that MSCs interact with endogenous c-kit+ CSCs via connexin-43 gap junctions and stimulate their proliferation and differentiation [21] .1 EF units versus baseline (n  =  8). The preliminary data. the discovery of microRNAs as regulators of cardiovascular biology and stem cell differentiation have made them attractive targets to optimize cell-based therapies [41] . Another extremely promising cell-based therapeutic for chronic ischemic cardiomyopathy and heart failure are cardiac-derived stem cells. which will potentially translate into better clinical outcomes www.3  ±  2.futuremedicine. These findings support the initiation of clinical trials in patients with chronic ischemic cardiomyopathy. Two novel and exciting possibilities are the combination of different stem cells [40] or of cell and gene therapy [9. reported at the 7th International Symposium on Stem Cell Therapy and Cardiovascular Innovation. and LV dysfunction (mean baseline LVEF was 39 ± 12%) were randomized to receive infarct-related coronary artery infusion of cardiosphere-derived cells or standard care 1. we hypothesized that combination therapy may provide greater cardiac structural and functional repair. including the target patient population.com . A total of 25  patients with ischemic future science group heart disease. delivery method. Various approaches to inhibit local inflammation and promote cell survival and tissue regeneration are being investigated. with an increase in LVEF of 12. infarct size (mean infarct weight assessed with cardiac MRI) decreased by 24% at 4 months and 30% at 1 year (n = 7).5 ± 2. the recently completed CADUCEUS trial [20] is a Phase  I randomized clinical trial of cardiospheres as a cell-based therapeutic. [9. as assessed by cardiac MRI.36–39] . SCIPIO. uncertainties remain regarding the most efficacious cell type.10.8% (n = 14) at 4 months after infusion of CSCs. „„ Novel in vivo differentiation & imaging approaches Recent studies employing animal models of ischemic heart disease 21 Future perspectives Although there has been significant progress in the clinical translation of cell therapy over the past decade. In addition. in contrast to the study of cultureexpanded c-kit+ CSCs. However. regional contractility and regional systolic wall thickening was observed 6  months following cell therapy. cell dose and CSC-specific characteristics. These dramatic initial results are highly encouraging and warrant further investigation in larger studies. or transfection of stem cells with prosurvival or antiapoptotic genes prior to cell delivery [9. homing and engraftment. Nevertheless. Furthermore. Adding to the complexity. A reduction in scar mass (28% by 6  months and 42% by 12 months) and an increase in viable heart mass.9 to 38. LVEF significantly increased from 30. There was evidence of an even greater effect at 1 year. showed a reduction in infarct size and an improvement in maximum oxygen consumption and exercise capacity [31] . Ischemia creates a hostile microenvironment due to locally expressed proinflammatory and proapoptotic cytokines inducing cell death. the encouraging results from these two  clinical trials provide rationale for larger randomized trials that will extend these observations to test whether cardiac-derived stem cell infusion produces sustainable clinical benefits in patients with ischemic heart disease. cardiospheres did not augment parameters of integrated cardiac performance such as LVEF. Recently. end-diastolic volume or end-systolic volume. including preconditioning by in vitro incubation of stem cells with prosurvival factors. there is growing evidence that stem cells harvested from patients do not produce the same benefit as those from healthy individuals [35] . whereas no change in LVEF was evident in the control patients (n  =  7). Cardiac-derived stem cells under investigation include cells that express the SCF receptor c-kit (CD117) [32] and multicellular clusters named cardiospheres [33] .3 ± 1. On the other hand. demonstrated that intracoronary infusion of autologous c-kit+ CSCs is safe and effective at improving LV systolic function and reducing infarct size in patients with heart failure (LVEF <40%) after MI who had undergone coronary artery bypass grafting [19] . One of the major challenges of cellbased therapy is the survival of cells after delivery into the recipient tissue microenvironment.36–39] . which are currently in the planning phase. this combination of cell types have demonstrated efficacy in eliciting a favorable remodeling response in preclinical models. these issues highlight the need for further investigation of the mechanisms underlying stem cell survival. successful percutaneous coronary revascularization. Notably. plasticity and function.34] . In addition.10. Collectively. source and quantity.36–39] . pharmacologic and genetic strategies are being developed in an effort to improve stem cell survival. Both can be harvested from patient endomyocardial biopsies and expanded ex vivo to generate large numbers of autologous cells that can be delivered back to the patient [33.

Future studies in large animal models are required to investigate further the safety and efficacy of this novel approach for endogenous cardiac regeneration. regional contractility and regional systolic wall thickening at 6 months after cell therapy. a cocktail of four transcription factors (GATA4. Combination cell therapy ƒƒ Preclinical studies showed that the combination of MSCs and c-kit+ cardiac stem cells is more effective at reducing infarct size and restoring cardiac function than either cell type alone. (2012) 7(6 Suppl. ƒƒ The POSEIDON study (NCT01087996). they demonstrated that expression of these four  transcription factors reprograms nonmyocytes to cardiomyocytes in vivo and attenuates cardiac dysfunction after MI. Cardiac-derived stem cells ƒƒ The Phase I clinical trial SCIPIO demonstrated that intracoronary infusion of autologous c-kit+ cardiac stem cells is safe and effective at improving left ventricular systolic function and reducing infarct size in patients with chronic ischemic cardiomyopathy. Conclusion ƒƒ Future studies investigating the use of cell-based therapy in ischemic heart disease will focus on determining the most efficacious and safe cell type(s) and/or cell combinations to use as well as how cell–cell interactions mediate the cardiac regenerative effects. MEF2C and TBX5) reprogrammed adult fibroblasts into cardiomyocytes in vitro [42] . controlled study investigating intramyocardial VEGF-A165-stimulated adipose tissue-derived MSCs. will be presented as a late-breaking clinical trial at the American Heart Association Scientific Sessions in November 2012. double-blind. recurrent MI and stent thrombosis. the first randomized head-to-head comparison of autologous versus allogeneic MSCs delivered by transendocardial injection. demonstrated that a cocktail of four  transcription factors (GATA4. HAND2. engraftment and distribution of human induced pluripotent stem cell derivatives. Inc. using a retrovirus to deliver the transcription factors to the hearts of mice.) 22 future science group . a Phase I randomized clinical trial of cardiospheres as a cell-based therapeutic. suggesting that certain bone marrow cell populations may provide a greater regenerative benefit and determine clinical efficacy. Novel in vivo differentiation & imaging approaches ƒƒ In preclinical studies. double-blind. supporting the planned initiation of clinical trials in patients with chronic ischemic cardiomyopathy. Notably. ƒƒ A Phase II/III safety and efficacy study of autologous adipose-derived stem and regenerative cells delivered via the intracoronary route in acute MI patients (ADVANCE Study) has been initiated. demonstrated the safety and efficacy of percutaneous delivery with a transendocardial catheter delivery system of autologous bone marrow-derived MSCs or BMMNCs in patients with chronic ischemic cardiomyopathy. Exploratory analyses showed an improvement in left ventricular ejection fraction that was associated with higher bone marrow CD34+ and CD133+ progenitor cell counts. BMMNC therapy also reduced the incidence of death. ƒƒ The CADUCEUS trial. this is an exciting approach with potential for endogenous cardiac regeneration that Key points Acute myocardial infarction ƒƒ Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BMMNCs) prevents remodeling after acute myocardial infarction (MI) by reducing infarct size and left ventricular chamber enlargement.) in the setting of acute MI recently reported preliminary findings that an intravenous infusion of Prochymal within 7 days of an acute MI significantly reduced cardiac hypertrophy. ƒƒ In preclinical studies employing a large animal model of MI. MEF2C and TBX5) reprogrammed adult fibroblasts into cardiomyocytes in vitro and in vivo and attenuated cardiac dysfunction after MI. sodium iodide symporter transgene imaging was shown to be a feasible approach to follow in vivo survival. Med. placebo-controlled trial. Chronic ischemic cardiomyopathy & heart failure ƒƒ The Phase II trial FOCUS-CCTRN investigated the efficacy of transendocardial delivery of BMMNCs in patients with chronic ischemic cardiomyopathy. Regen. randomized. heart failure and rehospitalization for cardiac complications. stress-induced ventricular arrhythmia. a Phase I/II. Song et al. Osiris Therapeutics. ƒƒ The ongoing MyStromalCell Trial is the first randomized.Schulman & Hare have reported the development of novel approaches to enhance in vivo differentiation of endogenous cells into cardiomyocytes [42] . Although further studies in large animal models are required before translation into clinical trials. demonstrated a reduction in scar mass and an increase in viable heart mass. The patients exhibited improved regional myocardial contractility and decreased infarct size. HAND2. Prochymal®. and the improvements in regional function observed at 3 months after cell therapy predicted the degree of reverse remodeling after 12 months. ƒƒ A Phase II study employing bone marrow-derived allogeneic mesenchymal stem cells (MSCs. ƒƒ Results from the first eight patients of TAC-HFT.

303(3). Schulman IH. Fu JD. placebo-controlled trial investigating the safety and efficacy of transendocardial catheter delivery of autologous mesenchymal stem cells in patients with ischemic cardiomyopathy. RO1 HL084275. 16 Traverse JH. 165–171 (2010). 2(1). Eur. Am. Williams AR. Res. 14 Hare JM. 108(7). Hare JM. that is the question . Schulman IH. Benvenisty N. Delgado-Olguin P et al. 619–625 (2011). 11(2). Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Balkan W. JAMA 306(19). IH Schulman has no conflict of interest that could influence this work. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Hatzistergos K. Bone marrow therapy for 3 Suncion VY. Henry TD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Rationale and design for TIME: a Phase II. myocardial infarction . Lloyd-Jones DM et al. receives research support from Biocardia. 108(4). Cell 142(3). double-blind. Mushtaq M. In addition. Cell therapy for heart disease: to genetically modify or not. Laflamme MA. Nevertheless. Cell. Physiol. Vaughan DE et al. J. Nature 448(7151). Heart Circ. Res. P20 HL101443. Circ. 792–796 (2011). Zwadlo C.com .futuremedicine. H256–H270 (2012). 51(4). RO1 HL107110.Circulation 123(4). e18–e209 (2011). and perfusion in chronic heart failure: the FOCUSCCTRN trial . Ieda M. Hare JM. 8 nn 9 Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial . 100. 1717–1726 (2012). 13 Traverse JH. Velazquez DL et al. which various stem cells interact with host cells and/or each other and elicit their regenerative effects. Zhu WZ. 375–386 (2010). TAC-HFT is the first randomized. Pepine CJ et al. 23 future science group www. Conclusion In summary. (Orlando) 23(1). Physiol. engraftment and distribution of human-induced pluripotent stem cell derivatives in a porcine model of MI [43] . Willerson JT. Hare JM. particularly the best cell type(s) and/or cell combinations to use and elucidation of the mechanisms by Financial & competing interests disclosure JM Hare is supported by NIH grants: RO1 HL094849. Med. Cell-based therapy for prevention and reversal of myocardial remodeling. left ventricular function. cell-based therapy for ischemic cardiomyopathy and heart failure has emerged as a highly promising therapeutic approach that will expand the benefits obtained by current pharmacologic and revascularization approaches by directly reversing scar formation and promoting myocardial regeneration. Henry TD. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state . ­ References Papers of special note have been highlighted as: nn of considerable interest 1 5 Roger VL. Cardiol. Human embryonic stem cells and cardiac repair. J. Cancer Res. Cardiol. Res. 2110–2119 (2011). Fischer-Rasokat U. Echocardiogr. 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Adv. and the relative value of each approach will require future investigation. there are many additional benefits that cell therapy brings to bear. Stem Cells Transl. Xu C. 53–68 (2009). Hare J. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors . Clin. JAMA 306(19). 4 11 Leistner DM. The tumorigenicity of human embryonic stem cells . RO1 HL110737 and UM1 HL113460. JAMA 307(16). Trachtenberg B. 318–324 (2007). 15 Perin EC. Fuchs M et al. Schulman IH. J. Hauch KD. 133–158 (2008). 29–35 (2012). Circ. This study demonstrated the feasibility of repeated long-term in vivo imaging of viability and tissue distribution of cellular grafts in large animals. Mol. Ellis SG et al. The next stage of development for the clinical use of cell therapy should focus on investigating novel formulations. 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rab46@cam.). 26–31 . Department of Clinical Neuroscience. Med. frontotemporal dementia and amyotrophic lateral sclerosis. which target the aging brain.RESEARCH & DEVELOPMENT Research Update Stem cells and neurodegenerative diseases: where is it all going? Roger A Barker* Over the last few years there have been a number of major breakthroughs in the development of stem cells for diseases of the CNS. Cambridge CB2 OPY.uk Disease modeling: the use of inducible cells Using stem cells to dissect the cellular events underlying the genesis of different neurodegenerative conditions has gained prominence following the seminal demonstration that differentiated human somatic cells could be reprogrammed into a pluripotent state by the overexpression of a set of defined transcription factors [1.g.12. the capacity to engineer embryonic stem cells to defined neuronal fates in the absence of proliferative contaminant cells is now feasible. UK. we will discuss how these developments have come about.64 © 2012 Future Medicine Ltd Regen. While this is a useful starting point by which to define these diseases. ƒƒ Are heterogeneous with a complex etiology. In this review. In addition.ac. by so doing. Fax: +44 1223 331 174. particularly in those conditions that affect the more elderly. with a characteristic pathological pattern of protein aggregation – for example. the author will discuss how this technology of inducible stem cells has been used to better understand these diseases and how stem cells are being viewed for cell transplantation. such as Huntington’s disease (HD). (2012) 7(6 Suppl. the newly developed capacity to reprogram adult somatic cells from patients with these diseases has opened up new possibilities in this area. However. ƒƒ Have a pathology that is not confined to the neurons but involves glial cells and an inflammatory element. use patient-derived cells to study disease. University of Cambridge.: +44 1223 331 160. finding ways to better under­ stand and treat these conditions is a major challenge given the personal and economic costs. rather than just one neuronal network. which has to date been best modelled using either targeted lesions (e. *Author for correspondence: Roger A Barker. ƒƒ May have an effect on endogenous neurogenic processes.2217/RME. a lesion to the dopaminergic nigrostriatal neurons in the case of PD) or the generation of a transgenic murine model if the condition had a known Mendelian basis. In this short review. While these models are useful. they provide only limited information as the majority of patients with the most common neurodegenerative conditions have a non-Mendelian form of the condition with a complex evolving pathological process across networks of cells. typically with a significant vascular disease burden in the brain. This technology using induced pluripotent stem (iPS) cells means that cells can be grown from patients themselves that have the capacity to proliferate indefinitely in culture and a pluripotency profile that enables them ISSN 1746-0751 26 10. and what this means for the future of this whole field over the next few years. Tel. One of these has been in the ability to reprogram adult somatic cells to a more pluripotent state as well as directly to neurons and. it is nevertheless important to realize that these chronic neurodegenerative disorders: ƒƒ Have a much greater extent of pathological burden than was once recognized and as such these diseases target a whole range of different neuronal populations.2] . which opens up the possibility of using these cells for cell transplantation. are set to increase as the population ages. Parkinson’s disease (PD) and a host of other rarer conditions. KEYWORDS: n induced pluripotent stem cells n neural grafting n Parkinson’s disease n stem cells Chronic neurodegenerative disorders of the CNS.. in the case of PD the loss of the nigrostriatal dopamin­ ergic pathway and the presence of alpha synuclein-containing Lewy bodies. Robinson Way. Viewing these disorders as a discrete entity with a single pathology and core cell loss has been a useful first approximation. particularly in the context of Parkinson’s disease. Cambridge Centre for Brain Repair. Forvie Site. Each of these disorders is defined by the loss of specific populations of neurons. These disorders include Alzheimer’s disease (AD). ƒƒ Often display mixed profiles of pathology. As such.

27 .futuremedicine. Modeling disease with induced pluripotent stem cells or direct neuronal conversion. Two types of cell reprogramming strategies.com Induced pluripotent cells Neurons In vitro study Neurons Figure 1.future science group Somatic cells Somatic cells Stem cells & neurodegenerative diseases: where is it all going? www.

12] . providing genetically matched control cells to study the effects of that specific mutation. concerns with respect to their utility to do this have arisen (see above) in part because they are reprogrammed back to a more pluripotent stage. and what has this told us about neurodegenerative disorders? „„ Modeling disease with iPS cells iPS cells derived from patients offer a powerful in vitro model by which to study disease. (2012) 7(6 Suppl. A key finding is that relevant populations of neurons can be derived using this approach. By so doing. Again these reprogrammed induced neurons could be extremely useful for screening potential compounds for therapeutic purposes. such as most cases of AD and PD. However. they generated iPS cells that differ only in this gene (i. In this respect. and an increased susceptibility to degeneration and abnormalities in autophagosome function [10] . such as in PD or AD? The induction of pluripotency is accompanied by a progressive elongation of telomeres with passaging [17–19] . dopaminergic nigral neurons in the case of PD). Soldner and colleagues (2011) generated human iPS cell lines from a patient carrying the A53T (G209) mutation in the SNCA gene. The ability to make such cell lines and derive relevant neurons from them has now been achieved in a range of conditions but mainly from patients with Mendelian forms of disease such as some types of PD (see below) and AD. such as fibroblasts. most diseases of the CNS are now known to have multiple players. as well as in the cell derivation and differentiation processes [9. avoiding a pluripotent state [3] .10] . such as fibroblasts. Soldner and colleagues found no differences between the dopaminergic neurons derived from the iPS cells from PD patients and controls after 30 days in culture even though they showed that the cells had a true ventral midbrain dopaminergic neuronal phenotype [9. into this cell type has yet to be reported. However. In cases of diseases caused by a single abnormal gene. To overcome this issue. „„ Modeling disease with direct neuronal conversion While the use of iPS cells has shown great promise as a way to study disease in vitro. long-term culturing (<75 days) of these cells did reveal changes. several groups have developed methods that allow direct conversion of human differentiated somatic cells.11. This can be brought out by increasing the time spent in culture and/or the use of stressful stimuli. along with evidence of electrical excitability and transmitter release. if any. However. as these cells carry all of the necessary genetic risk factors for that disorder. the character of the derived neurons needs to be verified using not just immuncytochemistry but transcription profiles. which include differences in genetic background.) A further issue is whether iPS cells can truly be used to study pathologies found mainly in the aged CNS.. even in cells derived from aged individuals. The ability to model disease using the conversion of somatic cells from patients would therefore benefit from the development of cocultures of multiple induced cell lineages.Barker to be differentiated into any cell type. 28 The neurons derived using this approach often have a subtle pathology. In terms of the inflammatory components and the microglia. along with the genetic alterations introduced during the reprogramming process [13–15] . For example. These studies have largely used fibroblasts harvested from skin biopsies and a variety of different reprogramming and culturing regimes – techniques that are constantly being refined and improved upon.g. it excludes the use of iPS cell lines to investigate disorders with a more complex and mixed etiology. such that disease pathogenesis involves not just neurons but glia. The first proof-of-concept study converted mouse embryonic and future science group . this can be controlled for. as well as HD and some genetic forms of motorneuron disease and dementia [4–8] . the ability to make these different cell types and even induced neural stem cells from fibroblasts would be useful [23–26] .e. all of which argues for them still being relevant as an in vitro model for these disorders. such cells have been generated from mouse ES cells [27] .. All of this means that it is unclear whether deficits found in the cells truly relate to the disease state rather than the person or the derivation procedure itself. including different types of neurons. as well as studying disease pathways. thus rejuvenating the cells in a similar way to that seen in the embryonic stem (ES) cell state. Importantly though. Regen. For example. Another issue in modeling diseases using somatic cells is the variable biological characteristics of the cells. it is increasingly being recognized that such cells need to be shown to be true neurons of the type relevant for the disease state (e. as well as inflammatory cells. while this approach is appealing to study cellular mechanisms associated with Mendelian forms of disease. which they then corrected using zinc finger nuclease-mediated genome editing [16] . into functional neurons. Med. the telomere chromatin does return to a more mature state when differentiated and iPS cells also retain the DNA methylation patterns of their original state before derivation [20–22] . a gene that gives the cell its susceptibility for PD). So what has been shown with these two types of cell reprogramming strategies (Figure 1). More recently it has been shown that it is possible to directly reprogram human somatic cells into neurons without having to go through an intermediate pluripotent state [3] . These studies have drawn a number of important conclusions about the use of iPS cells to model disease. but the successful reprogramming of somatic cells. Finally. with a decrease in the number and length of neurites. In other words.

dedifferentiation. these cells may not be as immunogenically silent as once thought [42] .futuremedicine.com to show that it is possible to make functional dopaminergic neurons from iPS (and to a lesser extent induced neurons) cells. However. Human fibroblasts have also now been successfully converted into functional neurons by again overexpressing the same transcription factors [28] . and several subsequent studies have been undertaken to better optimize this approach [29. although the results from this approach have been somewhat inconsistent [34–36] . directly converted induced dopaminergic neurons from mouse fibroblasts have been transplanted into 6-OHDA-lesioned rodents [43. as well as limited fiber outgrowth and incomplete functional recovery after grafting [41] .30] . theoretically. but it is still not clear whether these cells can truly recapitulate the pathogenic processes in these disorders. the one condition where this has been most explored is PD [33] . immunological and practical issues with their derivation. which at most have involved a few hundred patients. which has raised the very real possibility that dopaminergic neurons derived from an ES cell source may be ready for early clinical trials in patients with PD in the next 5 years. a number of questions remain to be answered before they can be considered for use in any clinical transplant trial: QQ Do these cells really form mature nigral dopaminergic neurons with the necessary axonal outgrowth and arbor­ ization required of them to innervate the whole striatum when grafted? QQ How safe are these cells in terms of cell proliferation. implying that nigral dopaminergic neurons derived from stem cells sources should. to some. there are still issues of cellular proliferation within the graft. but by using combinations of factors known to be involved in normal dopaminergic neuronal development. These studies. although several proof-ofconcept studies have been undertaken www. This approach has been assessed in a number of studies.44] . However.36] . „„ Stem cell transplants Although a number of diseases have been thought suitable for this approach (e. these cells are a less attractive tool by which to study disease. Brn2 and Mytl1). although the results until recently were less impressive than older studies using fetal VM tissue [39] .38] . especially given the distributed neuronal pathology seen in all neurodegenerative disorders of the CNS. These induced neurons displayed appropriate neuronal properties such as the generation of action potentials as well as synapse formation [3] . have shown that VM dopaminergic neurons can survive long term in the PD brain and produce significant functional benefits in some patients [33. In addition. the ability to manipulate adult somatic cells from patients with neurodegenerative disorders of the aging CNS to neuronal phenotypes of relevance is now possible. a very recent and novel approach from the laboratory of Lorenz Studer has shown that dopaminergic neurons derived from a human ES cell source can have robust effects across a range of animal models of PD [40] . and this includes the cost. More recently. have the same capabilities. there are still concerns with their use. including ethical. Although the use of ES cells is very promising. It may be that they are ultimately better for doing this in neurodevelopmental disorders of the CNS [45–47] . The differentiation of human ES cells into dopaminergic neurons using standard future science group protocols has long been known to be inefficient. cell migration and the immune reaction they induce? QQ Do these cells retain a disease-specific vulnerability that will adversely affect their long-term survival and efficacy? QQ In the case of Mendelian forms of disease (including PD). To date. more realistically it is in the realm of disease modeling and drug screening that they offer most hope. and as a result iPS and induced neuron cells have been considered as alternatives for grafting. however. As the direct conversion does not go through a proliferative state. with some success. This ability to make large numbers of functional nigral dopaminergic cells from ES cell sources without teratoma formation has been shown in a number of in vivo transplant studies. While a number of different cell types have been tried to restore the dopaminergic deficits that lie at the heart of PD. the most successful approach to date involves the transplantation of fetal ventral mesencephalic (VM) tissue into the striatum of patients. can we repair disease-related mutations in vitro and transplant these cells successfully? QQ Can these cells be reprogrammed to replace all of the cell losses seen in this disease? Conclusion The ability to use stem cells to study neurodegenerative diseases has received much attention of late. the quantity of neurons that can be obtained is limited by the number of fibroblasts used as the starting material for conversion and thus. although again their ability to do this seems less than that seen with fetal VM tissue. its use in patients is limited in so much as this approach has only been done in AD patients with the generation of functional glutamatergic forebrain neurons from fibroblasts [31] . the yield of dopaminergic cells from such sources can be dramatically improved [37. and this may open up exciting new opportunities for cell grafting – although such a therapy would have to be shown to be competitive with the other treatments that are out there. HD [32]).Stem cells & neurodegenerative diseases: where is it all going? postnatal fibroblasts into functional induced neurons by the overexpression of three transcription factors (Ascl1. 29 .g. and it has been shown that while it is possible to make functionally relevant nigral dopaminergic neurons from such sources. Nevertheless. Therefore..

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so studies of their replacement with stem cell products serve as a model for stem cell approaches to less accessible areas of the CNS.77 © 2012 Future Medicine Ltd Regen. a single layer of pigmented cells that plays a key role in maintaining the photoreceptor cells and the blood– retina barrier (Figure 1).org ‡ These authors contributed equally to this work. Furthermore. One Discovery Drive.12. by definition. quantitatively and accurately by visual acuity and visual field measurements. Loss of vision is feared more than premature death or cardiovascular disease. This has led to new clinical trials for several eye diseases that are yielding encouraging results. In this article we survey recent advances in stem cell-based therapies for ocular disease. Fax: +1 518 694 8187. USA *Author for correspondence: Jeffrey H Stern. Keywords: bone marrow stem cell n eye disease n human embryonic stem cell n human neural stem cell n induced pluripotent stem cell n limbal stem cell n retinal pigment epithelial stem cell n umbilical cord stem cell Due to the burden of eye disease. the neural retina. according to a recent Society for Consumer Research group survey. Rensselaer. Neural Stem Cell Institute. NY12144. Neural Stem Cell Institute. the clear tissue covering the front of the eye that helps focus incoming light.). Regenerative Research Foundation. NY12144.: +1 518 694 8188. Systemic complications from intraocular agents are rare. One Discovery Drive. With the blossoming of human stem cell research. Quantifiable visualization of the retina with resolution up to a few microns is routine using computerized fundus imaging. NY12144. regenerative treatments are now being developed that can help reduce this burden. Rensselaer. The key sites currently targeted for stem cell transplantation include the cornea. Sally Temple & Jeffrey H Stern* Vision loss is a major social issue. Rensselaer. age-related macular degeneration. evisceration or enucleation [6] . Stem cell types for eye disease clinical trials Human stem cells from a wide variety of sources are being explored for eye disease transplantation therapies (summarized in Figure 2). One Discovery Drive. Some of the transplants are aimed to directly replace lost or damaged tissue. advanced methods exist to assess the clinical meaningfulness of eye tissue transplant outcome. Regenerative Research Foundation. while others replace essential functions of a tissue and/or produce beneficial growth and trophic factors to slow the disease progress. and its relative accessibility. „„ Pluripotent stem cells Pluripotent stem cells are. Neural Stem Cell Institute. Barbara Corneo‡. The annual direct cost of medical care for the most prevalent eye disease. USA Sally Temple. which contains the photoreceptor cells that transduce light into neural electrical signals sent to the visual cortex. the eye is a prime target for stem cell transplantation therapies. In addition. visual function can be assessed rapidly. with more than 20 million people over the age of 18 years affected in the USA alone. Tel.2217/RME. Rensselaer. Positive results from animal studies demonstrate that stem cell-based transplants can preserve and potentially improve vision. NY12144. Med. Neural Stem Cell Institute. Timothy A Blenkinsop. 32–39 ISSN 1746-0751 . additional trials and longer-term results are anticipated to further develop ocular regenerative therapies. and the retinal pigment epithelium (RPE). able to generate all somatic tissues. USA Barbara Corneo. with good surgical access and the ability to visually monitor changes after transplantation being significant advantages [1] . Regenerative Research Foundation. was estimated at US$255 billion in 2010 with an additional economic impact of US$88 billion due to lost productivity and the burden of family and community care for visual disability. One Discovery Drive. The neural retina and RPE are CNS tissues. and the risks of overgrowth and tumor formation associated with intraocular stem cell transplantation [2–5] are mitigated by the ability of using laser ablation and in extreme cases. with the potential to revolutionize our approach to ophthalmic disease and damage. jeffstern@nynsci. (2012) 7(6 Suppl. laser scanning ophthalmoscopy and optical coherence tomography technologies.RESEARCH & DEVELOPMENT Research Update Ophthalmologic stem cell transplantation therapies Timothy A Blenkinsop‡. USA. 32 10. Regenerative Research Foundation. In the next few years.

which are essential for maintaining the cornea [13] . but have not yet been shown to generate neural retina or retinal pigment epithelium. Pluripotent human embryonic stem cells (hESCs) or the recently developed induced pluripotent stem cells (iPSCs).000 cells. UCSCs could slow degeneration through trophic factor release. causing accumulation of waste materials leading to RPE cell death. limbal stem cells produce corneal epithelial cells. prospective study proposed by Advanced Cell Technology. allowing both allogenic and autologous transplantation [14] . „„ Neural stem cells Human neural stem cells (NSCs) are typically derived from donated human fetal forebrain tissue. a need that stem cells can fulfill. an early report showed no 33 . NSCs are capable of producing cells that can substitute several key functions of these tissues and produce specialized trophic factors that could be beneficial [11] . hESC-RPE were generated by ACT collaborators according to good manufacturing practice (GMP) and their purity was determined by qPCR and immunostaining for RPE-specific markers [33] . AMD. spontaneously produced from hESCs. which is anticipated to reduce tumor threat. (ACT) to determine the safety and potential efficacy of subretinal injection of RPE cells.com development [28–30] or small molecules with similar function [31] improves the speed and efficiency of RPE production. future science group „„ Umbilical cord stem cells Umbilical cord tissue is a source of valuable stem cells in the blood and mesenchymal lineages [14] . „„ RPE stem cells The recently discovered stem cell in the adult human RPE layer [12] allows the generation of large numbers of RPE cells in tissue culture. „„ Bone marrow stem cells These have a similar potential to UCSCs. cobblestone epithelium that lies beneath the neural retina. „„ Limbal stem cells One of the earliest stem cells in ocular clinical trials. has enrolled the first three patients.Ophthalmologic stem cell transplantation therapies including every cell type found in the eye. nonrandomized. types of retinitis pigmentosa (RP). Moreover. Several blinding diseases. or Stargard’s disease (NCT01345006 and NCT01469832). but can be obtained from the adult patient. The use of newly developed techniques now enables elimination of exogenous reprogramming factors [10] . Banking umbilical cord tissue enables patient-matching. These cells are capable of producing neurons and glia. receiving a dose of 50. including agerelated macular degeneration (AMD). pluripotent state [7] . a genetic disease in which proteins involved in the visual phototransduction cycle are dysfunctional. and is being explored for production of other ocular cell types. albeit slowly and at low efficiency [25–27] . are characterized by dysfunction of the RPE [15] . Although umbilical cord stem cells (UCSCs) do not produce ocular tissues such as neural retina or RPE. This clinical trial enrolling 12 dry AMD and 12 Stargardt’s disease patients to receive uniocular subretinal injection of GMP-compliant hESC-RPE cells. providing essential support [16–19] . a monolayer of pigmented. Autologous surgery is challenging. An important concern in using pluripotent stem cells is unwanted cell overgrowth or tumor formation. Phagocytosis of labeled beads was used to demonstrate functionality of the GMP-compliant hESC-RPE cells. iPSCs made from a patient’s own cells could reduce the need for immunoprotective regimens posttransplantation. hence the rationale for RPE replacement. in patients with late-stage ‘dry’ AMD (the form of AMD without neovascularization. affects approximately 10 million Americans over the age of 50 years and is the leading cause of blindness in the elderly [20] . This concern is particularly acute for iPSCs. In 2011. polarized. However. Stargardt’s disease is the most common earlyonset macular degeneration. Lack of pluripotency markers and lack of teratoma formation were used to show negligible contaminant residual hESCs.futuremedicine.000 cells. In addition. At 4 months after treatment of the first two patients (one with dry AMD. These breakthrough discoveries have led to clinical trials to determine if such visual preservation can occur in humans. multicenter. RPE & photoreceptor diseases. „„ Pluripotent stem cells for retinal & RPE degeneration RPE arises spontaneously from pluripotent human stem cells. one with Stargardt’s). The most common RPE disease. Loss or disease can impair essential RPE functions such as the diurnal phagocytosis and replenishment of photoreceptor outer segments. bring new hope for eyereplacement therapies by producing ocular cells in essentially unlimited amounts. efforts are being made to detect and eliminate residual pluripotent cells contaminating the desired differentiated cell product.9] . Supplementing with growth factors that stimulate anterior neural plate fate and RPE specification during normal www. NCT01344993). RPE derived from pluripotent stem cells using a variety of methods can preserve vision after transplantation into animal models of retinal degeneration [32] . alternatives using RPE from other donors is limited by the amount of tissue available. the US FDA allowed a Phase  I/II open-label. and thus secondarily produce retinal dysfunction. Proof of principle for RPE replacement has been shown by pioneering surgical experiments [21–24] . Stargardt’s disease and gyrate atrophy (GA). which are produced from a donor somatic cell type by incorporating key genes that create a primitive. iPSCs readily form tumors when produced using oncogenic. permanently integrating gene-delivery vectors [8. Inc. Later groups will receive doses up to 200.

and a clinical trial is anticipated. and collaborators. this patient showed visual improvement.) [101] . nonbiodegradable polyester insert have been completed by a team led by Peter Coffey at the Institute of Ophthalmology in London. „„ Coming soon: transplanting a patch of hESC-derived RPE monolayer Given that the RPE is organized in vivo as a tight. RPE: Retinal pigment epithelium. These cells were transplanted into the subretinal space of the Royal College of Surgeons rat. mild improvement was seen also in the untreated eye. which has an RPE defect that prevents normal phagocytosis of the photoreceptor outer segments. Several tissues in the eye are being targeted for stem cell replacement. using GMPcompliant iPSC-derived RPE cells [28. teratoma. this is often compromised in a diseased eye. the preliminary results are promising and this pioneering hESC clinical trial will be widely watched. RPE layer Cornea Light Corneal epithelium Photoreceptors Neural retina Figure 1.38] . Surprisingly. including improved color vision and contrast/dark adaptation. Nevertheless. At the same meeting. visual improvement was observed (five letters of the Early Treatment of Diabetic Retinopathy Study chart). and collaborators at the London Project to Cure Blindness. (2012) 7(6 Suppl. it is possible that a transplant of pre-polarized RPE cells will integrate and function better than a cell suspension. abnormal growths. especially when the RPE. Corneo. Japan. Peter Coffey also reported production of GMP-compliant. Nevertheless. For the Stargardt’s disease patient. „„ NSCs for AMD In preclinical studies by StemCells Inc. „„ Patient-derived RPE Transplantation of patient-matched RPE cells reduces the necessity of immunosuppression.37] . NSCs isolated from second trimester brain tissue were selected and grown into a defined cell line (HuCNS-SCs). Preclinical studies in pigs using a hESCderived RPE polarized monolayer growing on a coated. Temple & Stern Eye groups are working to create a suitable matrix that maintains a stable RPE monolayer patch for transplantation. and no donor cells were detected.29. ACT has recently enrolled additional patients in the USA and Europe 34 It remains to be determined if visual gains observed are due to implanted cells or to a placebo effect. Several Regen. iPSC-derived RPE. Med. is damaged. potentially indicating that immunosuppression is needed for donor cell survival. future science group . this is the first announced clinical trial using cells derived from iPSCs. Another approach toward immunematching being developed in our laboratories at the Neural Stem Cell Institute utilizes the adult human RPE stem cell that can be derived from living patients for autologous transplantation of this tissue-specific stem cell. and whether immunosuppression is essential for transplant survival. while the retina has immune privilege [35] .Blenkinsop. At the 2012 International Stem Cell Research meeting in Yokohama. essential for the blood–retina barrier. UK and UC Santa Barbara. from reading 21 letters of the Early Treatment of Diabetic Retinopathy Study eyechart before treatment. The AMD patient did not follow the immunosuppression regimen to completion. in partnership with Pfizer [36. Interestingly. Masayo Takahashi of the Laboratory for Retinal Regeneration at the Riken Center in Kobe announced a clinical trial for early 2013 enrolling five  AMD patients. polarized monolayer. and is a widely used model of retinal degeneration. rejection or inflammation [34]. The implanted NSCs significantly improved photoreceptor survival and vision [39] . This could be accomplished using iPSCs generated from patients. to reading 28 letters 3  months after transplantation.

Based on these data. Umbilical cord RPE: Retinal pigment epithelium. Centocor Biotech (currently Janssen Biotech.42] . CNTO 2476. „„ UCSCs for RP & AMD UCSCs transplanted into the subretinal space of the Royal College of Surgeons rat were found to slow vision loss [40] . „„ Bone marrow stem cells for photoreceptor diseases Bone marrow-derived stem cells have been shown to rescue retinal www. these cells did not differentiate into RPE or other retinal cell types. administered using a microcatheter. an early-onset genetic disease involving degeneration of both cones and rods [43. Human stem cell sources explored for eye tissue replacement. clinical trials were started to determine the safety and efficacy of these cells in patients with eye disease.futuremedicine. and further studies are ongoing: in RP patients in Brazil (NCT01560715) and Thailand (NCT01531348). to evaluate safety and efficacy outcomes in patients with RP (NCT00458575). potentially by substituting for RPE functions. and in Brazil in both 35 . Based on this promising work. hESC: Human embryonic stem cell. in 2007. such as phagocytosis and/or by producing trophic factors that slowed the photoreceptor degeneration. but were still beneficial. to determine whether UCSCs are safe and can slow degeneration and preserve vision in this disease. Inc. One was conducted to evaluate the short-term (10 months) safety of a single transplantation of 10 × 106 bone marrow-derived mononuclear stem cells in three patients with RP and two patients with cone–rod dystrophy. announced the initiation of a Phase I/II safety and preliminary efficacy trial. iPSC: Induced pluripotent stem cell. Inc. In June 2012.com degeneration in mouse models [41. No detectable structural or functional toxicity was found. the study was terminated citing an ‘internal business decision’. began a Phase I/II clinical trial (NCT01226628) transplanting CNTO 2476 into the subretinal space of patients with AMD..Ophthalmologic stem cell transplantation therapies Bone marrow Fetal CNS Cornea Limbus hESC-RPE iPSC-RPE Oral mucosa Subretinal space Vitreous Figure 2. a subsidiary of Johnson & Johnson) began a Phase I clinical trial using their future science group patented UCSC line. In 2010. In 2010. Janssen Biotech. StemCells Inc.44] .

They showed that permanent restoration of a transparent. these cells can be transplanted to regenerate the patient’s cornea [45. can destroy the corneal epithelium. Conclusion Most ocular stem cell translational studies are at early stages – basic research. In addition to CNS tissue. NCT01619189. For patients in which the limbus is completely destroyed. Corneo. The limbus. Treatment of the iPSC-derived RPE with vitamin B6 helped determine the dose needed to restore enzymatic activity. Regen. there are a number of clinical trials ongoing for corneal transplantation of limbal stem cells from both autologous (NCT00845117. is damaged in AMD. Such iPSC models will be enormously valuable assets in the fight against eye diseases. „„ Disease modeling: GA iPSCs can be generated from patients with eye diseases to study disease etiology and produce ‘disease in a dish’ models valuable for drug screening. Corneal damage. NCT01619189. blinding genetic disease caused by dysfunction of a vitamin B6-dependent enzyme that results in deterioration of retina. In approximately 10% of patients with AMD. alternative [48] . are also being developed to replace those lost in glaucoma and other optic nerve disorders. aiding treatment of the donor [64] .57] . for example due to alkali burns. Once mounted on a soft contact lens. has spurred efforts to produce human photoreceptors from hESCs and iPSCs in sufficient purity and quantity for transplantation [52–55] . which could be especially important for patients who have lost both RPE and photoreceptor cells or who have otherwise suffered extensive loss of neural retina. Protocols for the generation of other neural retinal cell types. transplanted alone (NCT00845117 and NCT01237600). a ring of tissue at the edge of the cornea. Bruch’s membrane is compromised such that the choroidal vasculature invades into the retina. leading in most cases to vision restoration. the thick matrix that underlies the RPE. Preserving and restoring vision are key future science group . NCT01123044 and 36 NCT01562002). „„ Increasing the ocular target cell repertoire Vision improvement after transplantation of photoreceptors in animal models [49–52] . contains stem cells that divide and differentiate into the corneal epithelium over the lifetime of an individual. Italy. such as ganglion cells. (2012) 7(6 Suppl. In a much-anticipated recent report. iPSCs were derived in David Gamm’s laboratory from GA donor dermal fibroblasts and differentiated into RPE. In a notable series of experiments. are target tissues for modeling in stem cell cultures and could be used to aid eye repair and slow or prevent disease. Med.6% of eyes and was stable at 10 years [47] . or on amniotic membranes (NCT00736307. RPE cells can be delivered on a bioengineered Bruch’s membrane capable of preserving and restoring the relationship between the RPE and the choriocapillaris. although less successful. Corneal repair The corneal epithelium is essential for maintaining a clear ocular surface. choroid and RPE [63] . Yoshika Sasai’s group has shown that mouse and human pluripotent stem cells can generate differentiated. NCT­ 01619189 and NCT01123044) and allogeneic sources (NCT00736307. preclinical and Phase I/II trials – with successful longer term results from autologous limbal cell transplant serving as a beacon for what we might achieve with stem cell approaches.46] . Currently. such as trabecular tissue that regulates fluid homeostasis. renewing corneal epithelium was observed in 76. containing RPE and neural retina with the appropriate layering and orientation [56. such as the trabecular meshwork or the RPE monolayer.Blenkinsop. leading to defective exchange of nutrients and cell products with the underlying choroidal vasculature [59] . Graziella Pellegrini and Michele De Luca in Modena. allogeneic transplantation using limbal tissue from an allogenic donor is a suitable. presented the results of a 10-year follow-up of patients who underwent such autologous limbal stem cell transplantation procedures [47] . Several laboratories are working toward the establishment of such matrix materials with different properties of chemical composition. thickness. Recently. Administration of vitamin B6 is reported to benefit a number of patients. Temple & Stern AMD (NCT01518127) and ischemic retinopathy (NCT01518842) patients. so-called ‘wet’ AMD.) Future perspective Bruch’s membrane. Other stem cell types being tested for this application include cultured oral mucosal epithelial stem cells (NCT01489501 and NCT00491959) and bone marrow-derived mesenchymal stem cells (NCT01562002). To help repair the tissue and prevent disease progression. causing extensive loss of central vision. This remarkable. It will be exciting to see how such multicellular growths might provide a more sophisticated 3D transplant. 3D structures similar to the embryonic eye cup. GA is a rare. life-altering result demonstrates the enormous potential of autologous stem cell therapy. For example. incorporating multiple retinal layers. „„ Bioengineered eye tissues In order to build ocular structures. For example. bioengineers are incorporating biocompatible materials with stem cell products [58] . NCT01237600 and NCT01562002). „„ Multilayered transplants The normal 3D configuration of eye tissues should be recapitulated to ensure the best possible outcome. resulting in opacification and blindness [13] . topography and biodegradation [60–62] . porosity. non-neural ocular elements. In a remarkable series of studies. it was shown that limbal stem cells could be harvested from a healthy area of the limbus in an individual with a damaged cornea and expanded in vitro to form a stratified epithelium that stained positive for a corneal-specific marker.

as well as sensitive visual tests for measuring outcomes and a localized safety profile. ƒƒ The future of stem cell therapy includes the use of human stem cells as disease models. 45(12). Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 15 Lim LS. 295–305 (2012). Translating stem cell studies to the clinic for CNS repair: current state of the art and the need for a Rosetta Stone. SK et al. Cell Cycle 5(23). 861–872 (2007). 2748–2752 (2006). 802–823 (2010). Dorrell MI. Tanabe K. Cellular and Gene Therapies for Retinal Disorders (CTGTAC Meeting #52). Exp. 247–258 (2009). Tissue and Gene Therapies Advisory Committee. Capela A. 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Learn more at DiabetesResearch. collaborate. Through this collaborative. Camillo Ricordi (front) and Director of Stem Cell Development for Translational Research Dr. fast-track and cure-focused approach.” At the Diabetes Research Institute (DRI). we are dedicated to that same ideal and proud to serve as a co-organizer of the event. Its multidisciplinary teams include researchers. the DRI is committed to conducting relevant research that moves the most promising findings in the lab to patient application in the fastest and most efficient way possible. . the DRI is able to advance the newest biomedical technologies that have real potential to deliver a cure for diabetes. all working together to cure those now living with diabetes. cure.Scientific Director Dr. as well as a host of international partners. Juan Dominguez-Bendala are working to turn stem cells into insulin-producing cells. Focusing on translational research.org This year’s World Stem Cell Summit aims to “connect. engineers and clinicians.

or nano-encapsulation).g. which parallels the obesity epidemic. In these cases. T2DM is characterized by insulin resistance. this article focuses on emerging reprogramming and replacement approaches. (2012) 7(6 Suppl. Besides Type 1 and Type 2 diabetes mellitus. reprogramming (e. so that the immune system can no longer destroy the new insulin-producing cells introduced either by regenerating. Keywords: b -cell regeneration n b -cell replacement n b -cell reprogramming n diabetes n embryonic stem cell n induced pluripotent stem cell n islet transplantation n mesenchymal stem cell The most frequent form of diabetes mellitus (DM) is the Type 2 variant (T2DM).). Miami. Med. it is critically important to avoid any approach that is likely to increase Luca Inverardi.RESEARCH & DEVELOPMENT Research Update From cellular therapies to tissue reprogramming and regenerative strategies in the treatment of diabetes Camillo Ricordi*. reprogramming or replacement (e. reprogramming or regeneration from native precursors must occur in the absence of the lifelong immunosuppression that currently limits the indications of islet transplantation to the most severe cases of T1DM. The most severe forms of DM are generally linked to the Type 1 variant (T1DM). University of Miami Cell Transplant Center and Diabetes Research Institute. ricordi@miami. from the exocrine compartment of the pancreas). micro. the study of the endocrine compartment of the pancreas is of great translational interest. FL. as strategies aimed at restoring its mass could become therapies for glycemic dysregulation. USA Juan Domínguez-Bendala.. replacement of the insulin-producing cells. transplantation of pancreatic islets or stem cell-derived insulin-producing cells). the additional challenge of the underlying autoimmune condition means we must consider strategies that would restore self-tolerance or eliminate the effects of autoimmunity. USA. USA *Author for correspondence: Camillo Ricordi. As the latter has been extensively reviewed in recent months by us and others. 41–48 ISSN 1746-0751 41 . or hyperglycemic disturbances following the treatment of cancer and nesidioblastosis. Objectives of cellular therapies and regenerative medicine strategies for the treatment of DM are to reverse the disease condition and prevent the development of the severe chronic complications that over time can affect most organ systems in a large proportion of patients.edu 10. University of Miami Cell Transplant Center and Diabetes Research Institute. In T1DM.g. hyperglycemia and eventually dysfunction of the insulin-producing cells. However. over the years. which prevalently affects subjects in the adult and older age segments. drug-related diabetes following diabetogenic therapies. engineered microenvironment or selectively permeable physical barriers like those introduced by conformal. with a peak of incidence around 12–13 years of age.g. Miami.2217/RME. Abrogation of autoimmunity or its effects could be achieved by either tolerance induction strategies or immune protection (e.70 © 2012 Future Medicine Ltd Regen. FL. total or near-total destruction of insulin-producing cells (the b -cells contained in the pancreatic islets – Islets of Langerhans) occurs. and regeneration (replication and induction of endogenous stem cells).. For a successful therapy. we are witnessing an alarming increase in the number of children afflicted by this condition. University of Miami Cell Transplant Center and Diabetes Research Institute. FL. which can affect any age group but typically affects children and younger age segments.. Such strategies generally fall under one of the ‘three Rs’: replacement (islet transplantation and stem cell differentiation). This form of diabetes could be prevented in a significant portion of patients by lifestyle and diet preventive strategies. Luca Inverardi & Juan Domínguez-Bendala Diabetes mellitus represents a global epidemic affecting over 350 million patients worldwide and projected by the WHO to surpass the 500 million patient mark within the next two decades.12. Miami. insufficient insulin production occurs in the majority of patients affected by T2DM. However. For expansion of the indications for cellular therapies and regenerative strategies in diabetes.

which almost invariably describes the evolution of innovations in all fields of knowledge [1] . they add the ability to turn into virtually every single tissue of medical interest.21] . Advances towards obtaining a fully functional cell product in vitro are important because of the dangers associated with the transplantation of immature progenitor cells. Med. which has finally settled the trend somewhere between the initial expectations and the ensuing disillusionment. the above timeframe does not appear to be unreasonable (see www. However. when the description of a steroidfree immunosuppressive regime (the Edmonton protocol) seemingly solved the problem of long-term graft survival [3] . to true b cells than any other cell differentiation product described thus far from adult stem cells [17. The oftencited argument that ES cells must be inferior to adult stem cells just because they are not as abundantly represented in clinical trials is obviously misleading. In other words. Stargardt’s macular dystrophy and advanced dry age-related macular degeneration). A Gartner-like hype curve has also been seen in the readjustment of our expectations for this technology. the learning curve is expected to be short by the time we are able to safely differentiate stem cells into insulin-producing cells. There is a broad consensus that they are uniquely qualified to provide the large amounts of tissue required for therapeutic scaleup. it turned out that 5 years after the intervention. Funding for these programs dwindled significantly. which are delivered subcutaneously within an immunoisolation device. which remains the foremost cell therapy for T1DM. Expectations dropped precipitously through the next phase of the hype cycle. this study will focus on a few of the most recent trends in replacement and reprogramming that are shaping this rapidly evolving field.) . many of them dedicated to overcoming the regulatory issues inherent to the translation of any new therapy. eventually led to the current ‘plateau of productivity’. As the correction of our expectations has also been accompanied by the emergence of stem cell therapies. State of the art in cell-based therapy for diabetes The history of islet transplantation. which is as an invaluable testing ground for the next generation of cell therapeutics. efforts at improving islet transplantation are now being 42 re-examined under a more favorable light. however. but the ‘plateau of productivity’ we are currently witnessing is still extremely promising. USA. only 20% of the islet recipients were still insulin free [4] . Inverardi & Domínguez-Bendala morbidity and mortality rates beyond those already associated with the natural history of disease progression. The award of more than US$20 million to this project by the California Institute of Regenerative Medicine and the Juvenile Diabetes Research Foundation highlights the current interest in furthering research aimed at having a clinical ES cell-based product for diabetes within the next 5 years. Although their maturation still requires a last in vivo step [19] . A slow ‘slope of enlightenment’. as it ignores the fact that adult stem cells have been in use for more than half a century. there is still controversy regarding the candidate cell type(s) and approach that will ultimately take current therapies to the next level. This trigger was followed by a ‘peak of inflated expectations’.18] . The invention of the semiautomated method for islet isolation [2] was arguably the ‘technology trigger’ that made it feasible to consistently reproduce the often difficult and highly specialized process of separating the insulin-producing cells from the rest of the pancreas. has followed each one of the stages of the ‘Gartner hype cycle’. there is little doubt that they would have unconditionally embraced it. Unfortunately. By virtue of its overnight success. thus seamlessly expanding the applicability of islet transplantation beyond its current reach. the screening of compounds with the ability to enhance the differentiation outcome is still yielding very promising results. chiefly the formation of teratomas [23] ..Ricordi.clinicaltrials. aptly named the ‘trough of disillusionment’. whereas human ES cells have been around for only 14 years [16] . To this unparalleled replicative potential. (2012) 7(6 Suppl. Novel T-cell-depleting strategies and other immunological interventions are now sufficient to maintain graft survival and function in a manner that stands comparison to the standard of wholepancreas transplantation [5] . The California-based company ViaCyte (CA. If detractors of ES cells had found one such similar cell type from an adult source. as well as TGF inhibitors and other small molecules [22] have been recently reported to improve the differentiation of pancreatic progenitors and insulin-producing cells. the direct reprogramming of cells to a pluripotent state is arguably the most surprising and over-reaching discovery future science group Embryonic stem & induced pluripotent stem cells The controversy that surrounds the use of embryonic stem (ES) cells for therapy is not a scientific one. Since the subject has been recently reviewed in depth [6–14] with a special emphasis on regeneration (the ‘third R’) [15] . A number of activators of the PKC pathway [20. and only a few centers kept pushing in the middle of a climate decidedly hostile for the concept of islet transplantation as a viable path to cure diabetes. Given the solidity of the reported preclinical data and the fact that ES cells are already in clinical trials for other conditions (e. formerly Novocell) has reported preclinical success with human ES cell-derived pancreatic progenitor cells.g. Insulin-producing cells of ES cell origin are arguably closer in nature Regen.gov for additional information on current ES cell trials [101]).

futuremedicine. These fibroblast-like cells are abundant in most human tissues [47] . One of them is umbilical cord blood. A series of well-defined characteristics that define them as a group [49. there is no denying that a breakthrough in b -cell differentiation similar to that already described for ES cells [17–19] appears less likely by the minute. the age of the tissue. some claim that MSCs obtained from eyelid surgery are the best. This finding would also be consistent with the purported ability of another neural crest-derived MSC. who described cord blood-derived MSC cells that exhibited a number of ES cell characteristics and responded similarly to a b -cell differentiation regimen [70] . Given that some form of immunosuppression will be needed anyway. at least two sources of MSCs have garnered special attention in recent months.. DNA minicircles [43] . and can be readily differentiated into fat. In this context.33] . A b -cell differentiation protocol first designed for human ES cells was adapted to iPS cells by Tateishi and colleagues who. which have been progressively replaced by episomal constructs [40] . the donor. it is hardly surprising that no significant breakthroughs have been reported – let alone reproduced – yet. It still remains to be seen if iPS cells will be of any practical use in the context of T1DM. or even the specific clone analyzed (within the same donor and organ) [51] .com . among them the lingering ‘memory’ of the parental cells from which they came [34] . for those who did not have their own cord blood harvested at birth or failed to save those precious baby teeth. There are strong arguments for and against the notion that all MSCs are one and the same. Unlike nonautoimmune conditions. one must consider that most studies have been done with a handful of cell lines. The unprecedented speed at which induced pluripotent stem (iPS) cells have become a staple in regenerative medicine laboratories is illustrated by the observation that.50] does not preclude a puzzling variability in their behavior that depends on factors as diverse as their tissue of origin. the potential expression of tumor antigens that could mediate the rejection of grafts even from autologous sources [38] or even the premature senescence of their derivatives [39] . Although ES cells are also not precisely known for the homogeneity of their behavior.Cellular therapies to tissue reprogramming & regenerative strategies in the treatment of diabetes this young field has seen thus far [24–31] . However. probably in conjunction with physical immunoisolation. we do not anticipate iPS cells to be in the running for the next diabetes therapy breakthrough any time soon. future science group fully characterized allogeneic ES cell source. Many thought that the intrinsic limitations of MSCs to differentiate along definitive endoderm (a turn they probably missed for good when they took the mesodermal path) 43 Better sources of mesenchymal stem cells? The majority of adult stem cells used in the context of regenerative purposes belong to the mesenchymal stem cell (MSC) category. a field in which we would be pressed to find any two groups studying the same MSC clone. This is not the case with MSC research.42] . If we add to this the more general consideration that ‘patient-tailored’ iPS cell therapies are probably too costly and impractical to even consider at this juncture for even far less complex conditions. not surprisingly. The above limitations notwith­ standing. the original excitement about this noncontroversial mix of adult and ES cells has waned significantly in view of some unexpected shortcomings. Indeed. Current efforts include standard chemical approaches. to differentiate along the three embryonal layers (including insulin-producing cells) [77] . the worrisome observation that the reprogramming process itself may be accompanied by the induction of genetic mutations associated with the activation of potentially oncogenic events [35–37] . the technology has seen the completion of its own Gartner hype curve [32. On the brighter side. The proponents of this type of cell contend that they derive from the neural crest. which is easily bankable [71–74] and offers the theoretical advantage of its ‘youth’. which is known to be home to multipotent cells throughout development [76] . Despite the cautious excitement caused by some of these findings. genetic manipulation and even in vivo maturation following systemic administration [52–70] . If we add to this the mind-boggling amount of cellular substrates being utilized (spanning from bone marrow and umbilical cord blood to periodontal www. This was one of the conclusions of a recent study by Prabakar et al. reported a similar outcome [46] . transducible proteins [41. their generation is no longer dependent on the use of translationally unfriendly viruses. cartilage and bone [48] . This has complicated tremendously the definition of a ‘gold standard’ of differentiation into b cells – a goal that many believe to be unrealistic. we may as well go for the easier alternative of an off-the-shelf. not all hope is lost: MSCs are anything but rare in adults. the second MSC source that currently commands the most attention is the adipose tissue. In particular. especially in the context of b -cell differentiation [75] . each one yielding cells of seemingly superior properties than the other). the latter extracted from numerous anatomical locations. modified mRNAs [44] and even small chemical agents [45] . barely 5 years after they were first described. grow well in plastic. iPS cell-derived b cells are not likely to fare any better against the faulty immune system of T1DM patients than their original b cells did after the onset of the disease. ligament and fat. in which a perfect match between the donor tissue and the recipient would be highly desirable. the periodontal ligament.

few would dispute that the reported results were nothing short of extraordinary. as of today. however. was largely unsuccessful when tested in a variety of tissues [84–86] . and not just insulin-secreting exocrine b -cell hybrids. NGN3 and MAFA ) [93] . New insulin-producing cells that were virtually indistinguishable from the native ones sprouted in the parenchymal vicinity of the site of the injection just days after the delivery of the above genes.Ricordi. a phenomenon that occurs naturally and is thought to foster cell-to-cell communication and the synchronicity of the glucose-mediated insulin secretion [94. Be this as it may. Future perspective Still in its infancy. however.) content and gene expression profiles) and the fact that they did not completely revert hyperglycemia in diabetic mice. cells co-expressing ductal and b-cell markers were identified [91] . Thus. After all. The ductal tissue is one such substrate that has shown promising results over the years. already explored successfully in the induction of pluripotency. it would seem that MSCs can only be coaxed up to a point. with the exception of the liver [87–90] . to the endocrine compartment of the pancreas.88] . Although they are present only transiently. Med. the more clinically friendly adenoassociated viruses had previously failed to induce reprogramming in a similar setting [96] . Of note. insulin Regen. if not perhaps even more critical. which is nowhere near the phenotype of a true b cell.88] . which are attractive characteristics in their own right and worthy of discussion in a separate review.. the choice of a starting material that was ontogenetically closer to the b cell (the acinar pancreas) turned out to be as critical. Inverardi & Domínguez-Bendala could be overcome by sheer in vitro manipulation. adenoviralmediated transduction of PDX1 into hepatic tissues in vivo has been shown to reverse hyperglycemia long term [87. even if diabetes was not completely reversed. when ductal tissue-rich leftovers of clinical islet preparations were cultured in conditions that foster ductal cell expansion. we anticipate an active period of exploration of nonviral alternatives for the delivery of the reprogramming agents. Considering that more than 90% of the pancreatic cells belong to the acinar compartment. NGN3 and NEUROD expression cassettes strongly upregulated insulin expression [92] . these cells appeared to be b-like. In this case. the acinar tissue of the murine pancreas can also be ‘reprogrammed’ by ectopically expressing a combination of three genes (PDX1. in which b -cell future science group . than the use of the three genes instead of just one.95] . Inspired in the pioneering work of Ferber and colleagues with ectopic Pdx1 in the liver earlier in the decade [87. However. we are progressively witnessing a diversion of differentiation studies in favor of research focused on the exploitation of the well-known proangiogenic and immunomodulatory properties of MSCs [78–83] . For starters. and perhaps reproducible ex vivo on cultured acinar cells (which. The role of PDX1 as a ‘master regulator’ in this process has led to the hypothesis that its ectopic expression might be able to induce pancreatic differentiation from various cell substrates. Indeed. mirroring efforts already reported for ‘vertical’ iPS cell reprogramming. the fact that such conversion was never full prompted new experiments looking at more ‘master’ genes (which may act 44 synergistically with PDX1) as well as cell substrates even closer than the liver. As recently reported by Zhou and colleagues. these viruses are known to elicit inflammation and other detrimental immune responses. This concept. this potential source of b cells cannot be dismissed. In this context. chiefly through a process of partial conversion of phenotype from hepatocytes to b cells. adenoviruses were used to deliver the three reprogramming factors. Still. This strategy. Owing to this. cells are known to behave in strange ways when taken out of their physiological context. the reprogramming process completely abrogated the original phenotype of the acinar cells. stem cell and regenerative strategies are of critical and timely interest for their potential application in all cases of insulin-requiring diabetes. but one that ultimately may only meet with success by means of more drastic phenotype-changing approaches (i. One possible explanation for this observation is that the newly induced cells failed to aggregate. The expression of the PDX1 gene in the foregut around the eighth day of embryonic development in the mouse is a hallmark of pancreatic specification. Lateral reprogramming The notion of reprogramming is an unlikely one: that a terminally differentiated cell can change its identity. It was an earnest and wellfought effort. Much remains to be done before this strategy could be clinically applicable. has also proven its worth in the context of b-cell neogenesis. are routinely discarded after every islet isolation procedure). Adult mouse and human ductal cells transduced with adenoviruses harboring PDX1. suggesting that some of the perceived shortcomings linked to the use of adenoviruses might paradoxically end up being fundamental for the success of this approach. these experiments provide the proof of concept that exocrine cell reprogramming is feasible. the field of b -cell regeneration for the treatment of diabetes has already generated numerous avenues of research. PAX4. (2012) 7(6 Suppl. including (but not limited to) T1DM and a large proportion of patients with T2DM. reprogramming). from a developmental point of view. Cellular therapies. At this point.e. Despite the lack of additional characterization (glucoseinduced insulin secretion. Blood glucose levels were significantly ameliorated in the treated animals.

and auto-immunity).Cellular therapies to tissue reprogramming & regenerative strategies in the treatment of diabetes dysfunction and requirements for exogenous insulin treatment would justify a biologic replacement or regenerative therapy. 12(6). Med. Endocr. Curr. A prediction about which of these avenues will ultimately become the treatment of choice may turn out to be a futile exercise. beta-cells: new sources for diabetes cell therapy. Med. 17 D’Amour KA. and more so because several of the strategies described herein may end up converging in a unified approach. Stem cells as a therapeutic target for diabetes. Agulnick AD. Dominguez-Bendala J.futuremedicine. Biol. 195–200 (2009). ƒƒ Mesenchymal stem cells are finally finding their ‘niche’ as adjuvants in the process of engraftment and/or endogenous regeneration. the Juvenile Diabetes Research Foundation and the Diabetes Research Institute Foundation. 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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. we could envision a strategy in which recipientspecific iPS cells are differentiated into b cells in vitro and then cotransplanted with adult MSCs (also isolated from the patient) for improved engraftment and function. et al. Aguayo-Mazzucato C. 214–227 (2009). Mansouri A. Harvard Business Press. Pancreatic Stem Cells. Am. Financial & competing interests disclosure C Ricordi. Morphol. Humana Press. 1534–1541 (2005). First report on the semi-automated method of islet isolation that helped standardize the procedure across the world for research and clinical applications. 8(11). N. Rev. Tyagi SC. Insulin-producing cells derived 2 6 7 8 from stem/progenitor cells: therapeutic implications for diabetes mellitus. Transplant. Rev. Kandaswamy R. 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Careful attention should also be directed to the assessment of the risk/benefit ratio associated with the selected cell product or regenerative/reprogramming strategy. Embryonic stem cell lines derived from human blastocysts. Stem cell therapy for Type 1 diabetes mellitus. Five-year follow-up after clinical islet transplantation. 731–741 (2012). Cell. 461–477 (2010). nn 9 Ricordi C. 2060–2069 (2005). How to make beta cells? Curr. Ther. 21(6). Diabetes Rev. The selection of the most appropriate source for insulin-producing cells is still not defined and the selected alternatives between replacement. 30(3). Academic Press. J Domínguez-Bendala and L Inverardi acknowledge funding from the NIH. Lacy PE. future science group www. Ricordi C. Fenn J.com 45 . Hebrok M. 23(12). 5 Reprogramming into pancreatic endocrine cells based on developmental cues. reprogramming and regeneration strategies should be further developed in preclinical model systems and tested in pilot clinical trials. Raskino M. 6(3). while carefully assessing cost–effectiveness and the relative potential for scale-up. 15. Parallel advances in immune-modulating approaches will undoubtedly foster the ultimate therapy in which the cells that are either replaced or regenerated are protected from the immune system of the patient (allo. 727–732 (2009). Paty BW. Shapiro SS 3 Shapiro AM. 184–190 (2010). Collombat P. Noguchi H. USA (2008).

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Long-term observation of patients with SCID-ADA has shown that cellular gene therapy is safe.10] . However. A number of children big setback for the field. gene data provides evidence for persistence correction has been clinically tested in of transduced T-cell lineages at least a number of other monogenic blood/ 3–5 years later and even up to 12 years immune disorders. There is now reason to believe that momentum in the field has reached the point where the successes will be more frequent. levinebl@mail.: +1 215 573 6788. The use of gene-modified cells has opened new avenues for engineering desired cell properties. Cell gene therapy for correction of genetic disorders The first use of gene-modified cells was for correction of an inherited missing gene function by autologous transplantation of gene-modified hematopoietic stem/progenitor cells (HSPCs).9] . Long-term follow-up In the last two decades. and for tracking cells and controlling cell persistence after transplantation. Alexey Bersenev.12. approximately 100 transplants of gene-modified CD34 + hematopoietic cells have been performed around the world [2.cells. As a monogenic disease. Long-term results of the early trials.12] .of viral vectors and other approaches to modified hematopoietic cells and showed gene modification of HSPCs are now functional recovery of myelopoiesis and in development and clinical testing to resolution of infections [8. such as X-linked after transplantation [1] . 50–56 ISSN 1746-0751 .med.13] . Since that time.71 © 2012 Future Medicine Ltd Regen. (2012) 7(6 Suppl. Philadelphia. Keywords: cell therapy n clinical trial n gene therapy n immunotherapy In this article we will review some of the key developments in cell engineering by gene transfer. The T-cell trials.5] .2217/RME. The University of Pennsylvania Perelman School of Medicine. New generations with CGD have been treated by gene.3. Philadelphia. Rapidly dividing cells of the immune system and especially T lymphocytes are affected. of gene insertion to hematopoietic stem Transplantation of autologous gene. respectively [2. and hint at additional future clinical applications. Department of Pathology and Laboratory Medicine.). the effects of the transgene used transduced CD34 + cells led to in this treatment. USA *Author for correspondence: Bruce L Levine. Fax: +1 215 615 4718. it was a syndrome [7] . PA 19104. Although most of the leukemia cases in patients with Wiskott–Aldrich have been successfully treated.4. the improve safety [2. were published recently [6] . PA 19104. Tel. Med. Adenosine deaminase (ADA) deficiency results in a buildup of cellular dATP and prevention of DNA synthesis. A study in very promising. These include the early clinical results of cell gene therapy use of self-inactivating retroviral vectors of monogenic immune disorders are and lentiviral vectors [12. summarized in Box 1. Overall. USA.upenn. which utilized gammaretrovirus-­ proliferation seen in the SCID-X1 trial mediated gene therapy in autologous is likely due not only to insertional hematopoietic CD34 + cells in SCID-X1 mutagenesis but also some combination patients.RESEARCH & DEVELOPMENT Expert Focus Convergence of gene and cell therapy Alexey Bersenev & Bruce L Levine* Gene therapy and cell therapy have followed similar roller coaster paths of rising public expectations and disappointment over the past two decades.3] . leads were able to recover immune function and many have been able to reduce or discontinue enzyme-replacement therapy and significantly improve their quality of life. some defect in the IL-2 receptor g chain SCID cases of gamma-retrovirus-induced (SCID-X1).edu 50 10. Department of Pathology and Laboratory Medicine. and the profound functional correction of immune cells immunosuppressed status of the patients and resolution of clinical symptoms [10] .11. for the use of cells as vehicles for gene delivery. The University of Pennsylvania Perelman School of Medicine. The majority of patients mice comparing the tumorigenicity of to effective immunological and metabolic correction and can be an alternative to conventional HSPC transplantation [1. chronic granulomatous acute leukemia and myelodysplasia were deficiency (CGD) and Wiskott–Aldrich reported in the SCID-X1 and CGD syndrome. severe combined immunodeficiency (SCID)-ADA was a prime candidate for gene therapy and the first-in-human studies were performed in the early 1990s [1] . Some notable recent clinical developments in cellular engineering by gene transfer offer lessons on how the field has emerged.

uncontrolled enhanced function is not so good. including complete www. appears not to be a general feature of gammaretroviral vectors in this cohort with a combined total of >500 years of subject follow-up. by one group targeting folate receptor in ovarian cancer [19] . perhaps due to low levels of in vivo persistence. Our center is conducting a clinical trial utilizing the CAR T-cell approach targeting the CD19 antigen in B-cell leukemia and lymphoma (NCT00891215). trafficked to bone marrow and continued to express functional CARs that have persisted at high levels.25] . This was the first trial using lentiviral vector technology in cancer and the first to include the 4–1BB signaling domain. Notable developments in the convergence of cell and gene therapy. while on normal cells expression is limited to the kidney and the biliary tract. off-organ liver enzyme elevations and cellular and humoral immune responses against the CAR and vector [21] . In a series of trials testing a gp120directed CAR in HIV-positive study subjects. Correction of a faulty gene and/or missing function ƒƒ The earliest application.17]). In a trial testing CAR T cells targeted against CD19 in B-cell lymphoma. This was attributed as the most likely cause of death and ‘possibly related’ to CAR T-cell infusion [27] .futuremedicine. However. Two recent studies have reported fatal serious adverse events following CAR infusion. CARs use patientor donor-derived lymphocytes that are gene modified to express chimeric receptor genes. Early clinical trials assessing CAR T cells against B-cell malignancies yielded somewhat disappointing results. we recently reported decadelong persistence of CAR T cells [26] .Convergence of gene & cell therapy retroviral vectors to lentiviral vectors demonstrated that lentiviral vector gene transfer into hematopoietic stem cells was not tumorigenic in contrast to retroviral vectors [14] . This combines the effector functions of T lymphocytes with the ability of antibodies to recognize surface antigens with high specificity in a non-MHC restricted manner [18] . In children. primarily in CD19 + and CD20 + hematologic malignancies [17] . the risk of death in patients with SCID-X1 who do not have a tissue-matched donor for HSPC transplantation is unfortunately higher than the observed rate of leukemias in these early gene correction studies. These two patients have a continuing remission at >20 months following CAR infusion and additional patients have recently been treated. There are a number of clinical trials testing second-generation CARs that incorporate multiple signaling domains. Gene transfer of safety switches adds a measure of control ƒƒ A complement to redirecting target specificity is directing/redirecting cell trafficking or tropism Redirecting immune cell function One strategy to produce gene-modified cells redirected towards pathogens is the chimeric antigen receptor (CAR) approach first described by Eshhar [15] . universal targeting vectors can be constructed. Figure 2 shows our method for the production of CAR T cells. Insertional mutagenesis. Preliminary results reported from this trial are promising as three out of three patients with advanced chronic lymphocytic leukemia treated gained clinical benefit. one patient demonstrated elevated cytokines that may have been secondary to a prior subacute infection exacerbated by the immune suppression associated with chemotherapy-induced lymphodepletion. The CAIX is instructive in that the antigen targeted is overexpressed on renal cell carcinoma. CAR T cells have the potential to last many years and provide a memory response against tumor or infection. CARs express an extracellular ligand generally derived from an antibody and intracellular signaling modules derived from T-cell-signaling proteins (Figure 1 and reviewed in [16. Infusions of the CAIX CAR T cells were initially well tolerated. The second case was a trial in cancer patients with overexpressing HER-2/neu tumors treated with an 51 . Thus.23] . Box 1. This study also indicated the safety of gene-modified T cells. The engineered T cells expanded more than 1000fold in vivo. The authors concluded that the liver toxicity was most likely due to the reactivity of CARs against the target future science group antigen expressed on normal biliary tract tissue.com remission in two out of the three patients [24. after several infusions most patients developed on-target. The first clinical trials of CAR-based T-cell therapy for cancer were reported in 2006. and a separate center targeting carbonic anhydrase IX (CAIX) in metastatic renal cancer patients [20] . and perhaps to this day what the lay public associates with the term ‘gene therapy’ Redirecting cell function ƒƒ Increases the number of cells that can fight disease through gene transfer to redirect and enhance function Engineering HIV resistance ƒƒ Gene transfer of a chimeric enzyme recapitulating a naturally occurring mutation that renders homozygotes highly resistant to the most commonly transmitted tropic strain of HIV Designing cell fate: safety switches & pathotropism ƒƒ Enhanced function is good. While a degree of risk of insertional oncogenesis in HSPCs is likely to remain with currently available gene vectors. results from a clinical trial using CAR’s directed to the diasialoganglioside GD2 in refractory neuroblastoma have demonstrated safety of GD2-CARs [22. which caused leukemia in HSPC-based trials.

TCR: T-cell receptor. anti-HER-2/neu CAR [28] . Two clinical trials have been conducted to test the effect of these genome-modified cells on safety. Genetic epidemiology has led to the development of strategies to target HIV cellular entry. CCR5 was therefore recognized as a potential drug target and several drugs are now approved to block HIV cellular entry. T cells can be engineered to have retargeted specificity for ­ tumors. USA). future science group Figure 1. CCR5 ZFN modification in CD4 T cells may render a survival advantage to these cells in HIV-infected subjects. Endogenous T cells express a single heterodimeric TCR (left). engineering HIV resistance through ribozymes. and less expensive than a lifetime of antiretroviral drug therapy. and blockade of viral entry into immune cells by engineering HIV-resistant T cells [30] . which explains why certain high-exposure risk patients remained HIV-resistant [31] . Chimeric antigen receptor T cells target surface antigens in an MHC-independent fashion. Designer zinc finger nucleases (ZFNs) are chimeric DNA-binding proteins/endonucleases that can edit the genome by targeted DNA doublestrand breaks [34] . and effect on HIV viral load (NCT01044654 and NCT00842634). Several years after this treatment. fortunately followed by recovery and remission. We previously showed that engineered ZFNs targeting human CCR5 efficiently generate a double-strand break at a predetermined site in the CCR5 coding region upstream of the natural CCR5 D32 mutation. patients remain 52 . A recapitulation of the naturally occurring mutation was reported in an HIV-positive patient in Berlin diagnosed with leukemia who underwent a HSPC treatment with a matched unrelated donor also selected for the CCR5 D 32 mutation [32] . or T bodies. conduct and monitoring after infusions. These cases point out the potency of this approach and the need for careful design. at risk for long-term comorbidities and uniformly exhibit recurrent viremia when antiretroviral therapy is discontinued due its failure to eradicate the viral reservoirs [29] . The safety results have been encouraging and additional clinical trials are planned. The development of cell-based engineering approaches inducing robust CD4 + T-cell resistance to HIV infection would be significantly less expensive and less toxic than allogeneic HSPC transplant with a CCR5-/. increases in CD4.) Engineering HIV resistance Despite the profound successes of combination antiretroviral drug therapy in HIV. ZFN-modified T-cells show a marked growth advantage when challenged both in vitro and in vivo with CCR5-tropic HIV [35] . there is no detectable HIV in this patient in multiple biopsied tissues [33] .25] . combinatorial approaches. consistent with a cytokine storm. A naturally occurring mutation of the HIV cellular entry coreceptor CCR5 Regen. The patient demonstrated a dramatic rise in proinflammatory cytokines. initiating multisystem organ failure. efficiently and stably modify the CCR5 locus. composed of antibody extracellular domains and T-cell-signaling intracellular domains such as 4-1BB and CD3z. Cellular gene therapy approaches developed for treatment of HIV include engineering HIV resistance at various points during the HIV infection cycle. the generation of cytotoxic CD8 + T cells expressing HIV-specific T-cell receptors. ZAP70: Zeta-chain-associated protein kinase 70 kDa. In our study at the University of Pennsylvania (PA. The patient received a lymphodepleting regimen followed by 1010 HER-2/neu CAR T cells.(D32) donor.Bersenev & Levine (D 32) was described in 1996. persistence and trafficking of CCR5 ZFN modified T cells. Chimeric antigen receptor T cells are created by the introduction of genes that encode chimeric tumor antigen-specific receptors. we reported delayed tumor lysis syndrome after CAR T-cell infusion [24. Med. (2012) 7(6 Suppl. Transient expression of the CCR5-targeted ZFNs was sufficient to selectively.

and a randomized open-label Phase III trial is in progress (NCT00914628). ontarget but off-tumor immune reactivity and graft-versus-host immune reactions. such as inefficient migration. lead to elimination of the transduced cells. This approach has been clinically tested in donor T-cell infusions after hematopoietic stem cell transplantation in leukemia. A different safety strategy is to generate chimeric antigen receptor-targeted T cells using RNA [39] .com has been induced in caspase-9 genemodified T cells administered to patients with GVHD [38] . Safety switches & pathotropism The ability to design and control cell fate after transfusion could prevent complications. which when activated by a drug. Cells are expanded ex vivo for approximately 10 days when beads are removed and the cells are washed. an otherwise bioinert smallmolecule dimerizing drug. concentrated and formulated to the final cryopreserved cell product. A single infusion of the apoptosis inducer AP1903.futuremedicine. The engineered T cells were controlled by induction of a suicide gene in leukemic patients who had developed graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation and donor lymphocyte infusion. This approach avoids the use of integrating vectors and the potential for genotoxicity. The cells are infused following completion and review of quality control testing. A subsequent trial [37] showed that acute and chronic GVHD could be controlled. reduces the costs associated with retroviral and lentiviral vector production and testing. White blood cells are removed by blood draw or leukapheresis and T cells are stimulated with anti-CD3 and anti-CD28 mAb-coated beads in media supplemented with vector encoding the transgene. led to rapid elimination of 90% of transduced T cells with resolution of GVHD. excessive proliferation. One current approach to directing cell fate involves the introduction of so-called ‘suicide genes’. Another ‘safety switch’ approach has recently been studied where apoptosis www. Ex vivo process for engineered T-lymphocyte therapies. 53 . The first future science group clinical trials involved the gene encoding herpes simplex virus thymidine kinase as a ganciclovir-induced suicide gene [36] .Convergence of gene & cell therapy Autologous blood collection Infusion of T-cells Patient Antibody-coated beads Cell product Activated expansion gene delivery Bead removal and formulation Figure 2.

Recent work aims to control and direct cell trafficking or tropism for targeted delivery of a modified cell or prodrug. Sadelain M. Dunbar CE. development. ƒƒ Ex vivo gene transfer of safety switches adds a measure of control to genetically modified and adoptively transferred cells. This mimics a naturally occurring mutation that renders homozygotes highly resistant to the most commonly transmitted tropic strain of HIV. What began as elegant simplicity has now evolved into the creative combination of a variety of gene and cell engineering technologies. one can speculate that the first approved genetically modified cell products will be developed for clear unmet medical needs and orphan indications.) future science group . Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first Follow-up report on the first clinical trial of gene-modified T cells shows the persistence of these cells for 12 years in a highly selective in vivo environment of congenital adenosine deaminase Riviere I. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. The development of improved vectors and gene transfer technologies. Some cells. inexpensive and potentially less toxic way to test new construct designs and therapeutic targets. Gene modified cells or their progeny can persist for decades. regulatory approval. Alternatively. Blood 119(5).41] . and is a different paradigm in drug development compared with biologics or allogeneic cell therapies. 54 Regen. therefore. gene-modified cells can be detected in each patient more than 20 years after infusion (L Muul. ƒƒ Immune cells that are the target of HIV infection can be genetically edited to remove the most common coreceptor that HIV needs for cellular entry. Future perspective From the initial idea of gene therapy as gene correction. Hematopoietic stem cell engineering at a crossroads. Key points ƒƒ Gene-modified hematopoietic cells can correct a faulty gene and/or missing function. Clinical and commercial development of these technologies requires ‘outscaling’ and strict chain of custody practices. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. products that demonstrate efficacy where repeated courses of other conventional therapies have failed will spur investment. Soenen SL et al. redirects and enhances immune cell function. Financial & competing interests disclosure Bruce Levine has financial interest due to intellectual property and patents in the field of cell and gene therapy. such as mesenchymal stromal cells and neural stem cells. No writing assistance was utilized in the production of this manuscript. Cell migration may be engineered in combination with any of the approaches discussed above to improve homing and engraftment and engineered cells [43] . 1107–1116 (2012). gene and cell therapy has demonstrated the conversion of innovation into new therapies to treat our patients. (2012) 7(6 Suppl. n deficiency. along with improvements to ex vivo culture systems have enabled the field to blossom into a multiplicity of applications in a wide variety of diseases. proof-of-concept has now been demonstrated in a number of gene-modified cellular therapy approaches. The next step in gene and cell therapy will be to move more of these technologies into later-stage clinical trials and subsequent regulatory approval. Currently. genetically engineered stem cells could be used as a vehicle to deliver a gene encoding an enzyme that can convert a nontoxic prodrug into a toxic agent and. Blood 101(7). mediate killing of the tumor mass [42] . personal communication). A clinical trial of RNA-modified T cells redirected toward mesothelin is currently underway in mesothelioma (NCT01355965). 2563–2569 (2003). Within these diverse environments. Tuschong LM. This platform provides a relatively fast. This ability has been exploited to selectively deliver a therapeutic gene to metastatic solid tumors in animal experiments [40. This type of ex vivo genetic manipulation and adoptive therapy is most often autologous or directed. In the nearer term. Gene transfer and ex vivo expansion of the modified cells increases the number of cells that can fight disease. such as many of the monogenic diseases. and commercialization.Bersenev & Levine and results in self-limiting expression lasting only several days in vivo. Genetically modified neural stem cells that convert 5-fluorocytosine into the chemotherapeutic agent 5-FU are undergoing clinical trials in patients with gliomas (NCT01172964). Acknowledgements The authors would like to thank Anne Chew for thoughtful advice. ƒƒ Immune cells can be redirected to tumor or other antigens through the delivery of genes encoding chimeric antigen receptors. Med. References Papers of special note have been highlighted as: n of interest 1 clinical gene therapy trial. have the ability to specifically migrate to an inflamed area or a tumor. Based on pathotropism. described as ‘pathotropism’. 2 Muul LM.

Rev. 12(20 Pt 1). PRDM16 or SETBP1. have the ability to grow in the body in large quantities. USA 96(20). Med. Cooray S. Curr. 24 Kalos M. Following infusions. Clin. Schwarzwaelder K et al. Gaspar HB. 19(3). Aiuti A. Westwood JA. Curr. Science 302(5644).1038/ mt. Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to longterm immunological recovery and metabolic correction. therapy for primary immunodeficiency. this report captured 10  years of follow up. USA 86(24).Convergence of gene & cell therapy 3 Aiuti A.2012. Waks T. The T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Dotti G. 725–733 (2011). Engl. clonal proliferation of T cells was detected. Porter DL et al. Ott MG. Nat. Theobald N. n Initial report [20] and excellent follow-up [21] studies of gene-modified T cells 5 redirected to carbonic anhydrase IX. 21 Lamers CH. 97ra80 (2011).com 55 . Natl Acad. Educ. Waks T. N. Hauer J. Schmidt M. N. Med. 8 Kang EM. 14(11). Kalos M. Sleijfer S. Sci. J. Med. Sci. 6050–6056 (2011). Biasco L. Hematol. 6106–6115. Genet. Schmidt M et al. Transl. Two studies report on important studies following adverse clinical events [10. n Report on first three patients treated on a clinical trial using autologous T cells genetically modified with a chimeric antigen receptor (CAR) targeting a CD19 molecule on chronic lymphocytic leukemia cells. 6 Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome. Med. Lim A et al. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. 21(2). van Elzakker P Following the development of leukemia in patients with severe combined immunodeficiency that were administered retrovirally transduced hematopoietic stem cells. and one died. Soluble 10 Hacein-Bey-Abina S. 18 Pinthus JH. 11531–11536 (1999). 447–458 (2009). 2006. 17 Kohn DB. Cattaneo F. Savoldo B. 24(6).21] . 63(10). Savoldo B. Chimeric antigen receptormodified T cells in chronic lymphoid leukemia. Sci. Med.futuremedicine. Cesana D. Gilmour KC et al. 687–696 (2006). Dotti G et al. Ther. of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. However. and have been able to kill large quantities of chronic lymphocytic leukemia cells in the patients. Thrasher AJ. LMO2-associated clonal T cell proliferation in two patients after gene CARs on track in the clinic. 3(95). Brentjens R et al. Immuno-gene therapy of established prostate tumors using chimeric receptorredirected human lymphocytes. Immunol. 365(8). 23(6). Biotechnol. Engl. 363(4). Sci. Children with Wiskott–Aldrich syndrome treated with gene therapy saw their clinical condition markedly improve. CH June.2310 (2012) (Epub ahead of print). 12 Scaramuzza S. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. 415–419 (2003). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. 9 et al. Fu N. J. Schmidt Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first member(s) of the mesothelin/ megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. 20 Lamers CH. Med. Engl. Immune responses to transgene and retroviral vector in patients treated with ex vivo -engineered T cells. Med. State-of-the-art gene-based therapies: the road ahead. Riviere I. Med. Blood 118(23). M et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. Blood 117(1). 12(4). 22 Pule MA. 363(20). Program 682–689 (2009). J. Brentjens R. Stem-cell gene therapy for the Wiskott– Aldrich syndrome. 26 Scholler N. 13 Booth C. 10024–10028 (1989). Schwarzer A et al. augmented by insertional activation of MDS1-EVI1. n Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. 4 et al. A Phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Nat. Eshhar Z. 15 Gross G. Choi U. Soc. 432–438 (2011). e20–e22 (2006). von Kalle C. 401–409 (2006). Levine BL. 1264–1270 (2008). 19 Kershaw MH. Myers GD et al. 215–223 (2009). 355–364 (2010). n adenosine deaminase (ADA) gene therapy in children with severe combined immunodeficiency (SCID)–adenosine deaminase deficiency. Pediatr. Kaufman-Francis K et al. 7 Boztug K. 24(13). 3(97). 2470–2476 (2003). Galimberti S et al. Correction of X-linked chronic granulomatous disease by gene therapy. Cancer Res. acute leukemia developed in four patients. Mol. 23 Louis CU. Nat. Nat. 11 Kay MA.4] and London [5] groups demonstrating effective use of therapy for SCID-X1. Humoral and/or cellular anticarbonic anhydrase IX–chimeric antigen receptor T-cell immune responses were also observed. Opin. 95ra73 (2011). Opin. Bagg A. Engl. 659–666 (2011). Mol. Proc. 16 Sadelain M. n clinical experience. 316–328 (2011). Gene Hacein-Bey-Abina S. 1918–1927 (2010). 12(5). 360(5). Expression Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Cancer Res. Yang Y et al. Roncarolo MG. Gaspar HB. The data shows that a patient’s modified T cells can survive for many months after administration. Ten years of gene therapy for primary immune deficiencies. Hematology Am. Blood 115(4). doi:10. Reports from the Milan [3. Oncol. Natl Acad. 783–791 (2010). Proc. Parker LL 25 Porter DL. Transl. Schmidt M. Ther. future science group www. 14 Montini E. Following the report of the development of leukemia in SCID-X1 children treated with gene therapy [10]. Levine BL. Willemsen R. J. Clin. n promise and potential pitfalls of chimeric antigen receptors. Tracking T-cell clonality and integration site analysis is an important part of longterm follow-up in gene transfer studies. N. Vulto AG et al. N. Ripamonti A et al. J. 72–82 (2011). elevations in liver enzymes indicated on-target but offtumor toxicity. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.

692–698 (2009). 367–377 (1996). Kohn DB. Shin JY et al. Mol. Bernal Y. 19(6). Ferrand C. 41 Joo KM. Mol. Engineered cell homing. 1249–1258 (2011). 9(6). Yang JC. Rosenberg SA. therapies against HIV. Moon E. Spencer JA. Phillips JA et al. 34 Urnov FD. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a Phase I clinical trial. Riviere I. 17(3). Wang J. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Nat. Engl. Blood 117(10). Carpenito C et al. Blood 118(25) e184–e191 (2011). Biotechnol. J. Miller JC. 365(18). 38 Di Stasi A. Establishment of HIV-1 resistance in CD4 + T cells by genome editing using zinc-finger nucleases. apoptosis as a safety switch for adoptive cell therapy. Long- efficient endogenous human gene correction using designed zinc-finger nucleases. Engl. 646–651 (2005). 43 Sarkar D. Laurencot CM. 30 Rossi JJ. 39 Zhao Y. 26(7). Dotti G et al. 42 Kim SU. Kitano M. Mol. 31 Liu R. Stanghellini MT et al. Med. N. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a nonrandomised Phase I–II study. 843–851 (2010). Ther. Miller JC et al. Ther. hMSC- ME. 29 Siliciano JD. Med. Blood 97(1). Hofmann J et al. 32 Hutter G. Tey SK. Biotechnol. Yeh T. Lee YL et al. Jeung EB. Finzi D et al. Cancer Res. Mol. 2791–2799 (2011). neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases. 1673–1683 (2011). Choe S et al. Anticancer Res. Ther. Med. Nature 435(7042). June CH. 35 Perez EE. Potential tumor-tropic effect of genetically engineered stem cells expressing suicide enzymes to selectively target invasive cancer in animal models. Kim YB. 18(4). Human term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4(+) T cells. 727–728 (2003). Nowak D. Genetic Administration of herpes simplexthymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Ther. Sadelain M. 570–575 (2009). Nat. Lancet Oncol. 360(7). 70(22). J. Highly Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. 56 Regen. Kajdas J. Cho MH. 36 Tiberghien P. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiplyexposed individuals to HIV-1 infection. Mossner M et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. Hutter G. 28 Morgan RA. 37 Ciceri F. Lioure B et al. 808–816 (2008). 40 Yin J. 666–668 (2010). 9053–9061 (2010). 18(4). (2012) 7(6 Suppl. N. Cell 86(3). 489–500 (2009). Nat. Bonini C. 1444–1454 (2007). 25(12). Paxton WA. 63–72 (2001). Inducible Choi KC. 10(5). Med. Kim JK.) future science group . Dudley Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation.Bersenev & Levine 27 Brentjens R. mediated concurrent delivery of endostatin and carboxylesterase to mouse xenografts suppresses glioma initiation and recurrence. 1161–1169 (2011). Park IH. Moon JH et al. 31(4). 33 Allers K.

Med.).ADVOCACY & EDUCATION Article type INDUSTRY. (2011) 6(5 Suppl. Karl-Henrik Grinnemo & Richard Jove 10.XX.XX © 2011 Future Medicine Ltd Regen. COMMERCIALIZATION & COLLABORATION INDUSTRY Highlights Interviews Researchers and the translational reality Karen Aboody The Regenerative Medicine Coalition Frank-Roman Lauter Commentary Collaborations in Stem Cell Science Jonathan Thomas organization profile The International Translational Regenerative Medicine Center Mardi de Veuve Alexis.2217/RME. xxx–58 ISSN 1746-0751 57 .

IMPORTANT DATES Abstract Submission and Registration Begin: December 6. MA USA Visit www.isscr. 2012 Co-sponsored by ® .org/2013 for full details and information. 11th Annual Meeting June 12 – 15.Save the Date Join us in Boston for the ISSCR 2013 Annual Meeting — the world’s premier stem cell research event. 2013 Boston.

cellulardynamics.ac. (2012) 7(6 Suppl. USA (www. Human Embryonic Stem Cell Laboratories. Guy’s Assisted Conception Unit. hepatocytes and endothelial cells. Cells from a variety of tissue sources can be reprogrammed with genome nonintegrating episomal vectors under feeder-free conditions.mesoblast.12.). 2011–August 31.ilic@kcl. the company was named as the overall Gold winner in The Wall Street Journal Technology Innovation Awards by a panel of independent judges among 605 contestants in 16 categories. the company launched the new service MyCell™. a purpose-built manufacturing facility to be built by Lonza exclusively for Mesoblast and exclusive access to Lonza’s cell therapy facilities in Singapore. » The thunder from Down Under: Mesoblast Following acquisition of the USA company Angioblast and a strategic alliance with Cephalon. The company is progressing various products towards Phase III trials. including congestive heart failure. King’s College London School of Medicine.uk 10.78 © 2012 Future Medicine Ltd Regen. 59–63 ISSN 1746-0751 59 . WI. 2012 Business Development » Winning on multiple fronts: Cellular Dynamics International Cellular Dynamics International.com). including certainty of capacity to meet long-term global supply of its proprietary mesenchymal precursor cell products.com). Mesoblast has been granted approval to conduct clinical trials of adult stem cell therapies for a number of conditions. In October 2011.INDUSTRY. continued its domination in the area of induced pluripotent stem cells. neurons. In September 2011.tevapharm. MyCell is offering cell reprogramming. ­ Dusko Ilic. dusko. The alliance will provide Mesoblast with significant commercial advantages. www. genetic engineering and cell differentiation from customers’ samples. Australia-based Mesoblast (www. spinal fusion and bone marrow regeneration.com) has strengthened its position even further. Med. heart attacks.2217/RME. In addition to its portfolio of iCell® products. Division of Women’s Health. COMMERCIALIZATION & COLLABORATION Stem cell and regenerative medicine September 1. now wholly owned by Israel-based Teva Pharmaceutical Industries. human-induced pluripotent stem cell-derived cardiomyocyes. Mesoblast formed a strategic alliance with Lonza for clinical and long-term commercial production of Mesoblast’s allogeneic adult stem cell products.

the study’s primary end point. Med. no tumor formation or any other adverse effects were noted after the transplantation. It is similar in design to the US trial for Stargradt’s disease that was initiated in July 2011.000 RPE cells at Wills Eye Institute in Philadelphia (PA. Visual improvement was also noted.000 RPE cells in one eye at the Jules Stein Eye Institute at the University of California.willseye. USA. Regen. with cohorts of three patients each in an ascending dosage format (50. Additional information about these clinical trials can also be found at www.) “ ” 60 future science group . Preliminary data published in the Lancet in January 2012 demonstrated the safety of human embryonic stem (hES) cellderived retinal pigment epithelial (RPE) cells for the treatment of one patient with Stargradt disease and one with dry age-related macular degeneration. the first cohort of US patients with d r y age-related macular degeneration was completed. www.org) on August 1 2012. It will involve a total of 12 patients. www. The Phase I/II trial is designed to determine the safety and tolerability of human embryonic stem cellderived retinal pigment epithelium cells following subretinal transplantation in patients with Stargradt’s disease at 12 months. USA. NCT01344993 and NCT01469832).000).org).Ilic Clinical trials » Making history Advanced Cell Technology’s (MA. The promising preliminary results from the first cohort have positioned the Company well as they entered the second cohort and higher dosage in this landmark clinical trial.000–200. the second and the third patients with Stargradt’s disease of the first cohort in European clinical trials were treated at Moorfields Eye Hospital in London (UK). the study’s primary end point. The first patient of the second cohort was administered 100. Less than a year since the first two patients were injected with 50. Los Angeles (www. clinicaltrials.jsei. In parallel.advancedcell.gov (ID: NCT01345006.com) clinical trials in Stargradt’s and age-related macular degeneration so far look to be a success. No abnormal proliferation of the cells. The Phase I/II trial is designed to determine the safety and tolerability of hESC-derived RPE cells following subretinal transplantation in patients with Stargradt’s disease at 12 months. (2012) 7(6 Suppl.

CMS also issued a preliminary positive decision for the assignment of permanent Healthcare Common Procedure Coding System Q–codes for Grafix.Industry highlights » Into the clinic In May 2012. voiced their approval a few weeks later. newly diagnosed acute GVHD (ID:NCT00562497). for Americans 65 years and older. which was acquired in 2011 by French giant Sanofi (www. The freshly isolated human mesenchymal stem cells from the bone marrow aspirate are subjected to initial quality control testing for the stem cell potential and safety of the donor before further manufacturing.gov). Osiris’s division of biosurgery also made an important milestone. The Company has 49 issued US patents. cms. com). Medsafe. All clinical trials are ongoing in multiple centers throughout USA. moderate-to-severe Crohn’s disease (www. The codes will assist in facilitating reimbursement when Grafix products are used to treat Medicare patients with acute and chronic wounds. produced by Osiris Therapeutics. The Center for Medicare & Medicaid Services (CMS. com) received market authorization from Health Canada for the treatment of acute graft-versus-host disease (GVHD) in children. USA (www.futuremedicine. Treatment of recently diagnosed Type 1 diabetes mellitus (ID:NCT00690066) and acute myocardial infarction (ID:NCT00877903) are Phase II clinical trials.sanofi. New Zealand’s medical regulatory agency. Osiris has partnered with Genzyme Corporation.gov ID: NCT00482092). issued a transitional pass-through status with C– Codes being designated for Grafix®. MD.com 61 .genzyme. in the hospital outpatient department and ambulatory surgical center settings. The in-process intermediate then undergoes further manufacturing to yield a final product. This coverage decision will boost investor confidence in Osiris’s portfolio of stem cell-based therapeutics.osiris. “ Prochymal’s stem cells are derived from the bone marrow of prescreened healthy donors aged 18–30 years. to develop Prochymal as a medical countermeasure to nuclear terrorism and other radiological emergencies. USA (www. in combination with corticosteroids. All four are Phase III clinical trials. MA.clinicaltrials. www.000 doses can be manufactured from a single donation using proprietary isolation and amplification procedures. It is also the only stem cell therapeutic currently designated by the US FDA as both an orphan drug and fast track product. Prochymal is currently being evaluated in clinical trials for the following indications: treatmentresistant. The health of the donors is monitored for up to 5 years after donation to further ensure their health status. a human mesenchymal stem cell therapy product Prochymal® (remestemcel-L). each having one or more foreign counterparts.com). and some of them also in Canada. Nearly 10. Europe and Australia. especially diabetic foot ulcers.000 doses can be manufactured from a single donation using proprietary isolation and amplification procedures. which must pass stringent criteria before release and distribution. In addition. steroid-refractory ” future science group www. acute GVHD (ID:NCT00366145 and NCT00759018) and. Nearly 10.

The court’s ruling was on a legal challenge brought by Regenerative Sciences. The US District Court in Washington. “ ” Regulations » No way out In July 2012. US stem cell companies offering similar type of services may move to states with lesser regulations. a first-inclass.7 million by the Biomedical Advanced Research and Development Authority in the 62 Office of the Assistant Secretary for Preparedness and Response of the Department of Health and Human Services. Med. To avoid strict FDA regulatory monitoring. (2012) 7(6 Suppl.) future science group . the procedure should be considered routine medical practice and be subjected to state law.Ilic This ruling means that from a legal point of view stem cells are treated as drugs if they have been subjected to more than minimal manipulation. allogeneic. for the advanced development of CLT-008. Capital market and finances » Successful ride on government funding Privately held. continued its successful ride on government funding. the Company received US$16. The company claimed that the FDA should not be involved in monitoring and regulating Regenexx because the cells were minimally manipulated and all processing has been done in Colorado. Therefore. This ruling means that from a legal point of view stem cells are treated as drugs if they have been subjected to more than minimal manipulation. it is thought that.regenexx. cell-based therapy for the treatment of acute radiation syndrome. following this ruling. DC ruled that the FDA has the authority to regulate autologous stem cell therapies. USA (www. CO.com) when the FDA sought an injunction to take their product Regenexx™ off the market. venture capital-backed Cellerant Corporation. CA. This funding is in addition Regen. USA (www.com).cellerant. In September 2011.

com). secured a major pharmaceutical partner. with each partner owning a 50% share in the new company.futuremedicine. Japanese giant Otsuka Pharmaceutical Factory (www.9 million. aiming for marketing by 2016. bringing the total value of the contract to US$169. otsukakj. With development funding secured for DIABECELL®. eliminating the need for immunosuppressant drugs. including the T cells that cause GVHD. CLT-008 myeloid progenitor cells create a burst of mature cells and then die and clear out of the system in approximately 45 days. granulocytes and macrophages. Life Cell is poised to further develop its second xeno-cell therapy product NTCELL® aimed for treatment of Parkinson’s disease. Life Cell and Otsuka formed a joint venture in November 2011. “ ” future science group www. Both DIABECELL and NTCELL are encapsulated with IMMUPEL™. Treatment with NTCELL involves transplanting pig choroid plexus cells into the brain. which have lost the ability to self-renew and are restricted to creating mature myeloid cells: red blood cells.2 million previously awarded in September 2010. for co-development of its product DIABECELL® through Phase II and other pivotal studies. Diatranz Otsuka Ltd. Cellerant’s CLT-008 cell therapy product contains only early. if exercised by Biomedical Advanced Research and Development Authority. platelets. Under the terms of this revised contract. With development funding secured for DIABECELL. Once infused. Life Cell’s proprietary encapsulating technology.com 63 .Industry highlights to the existing contract valued at up to US$153. They cannot create lymphoid cells. The goal of the transplanted cells is to boost neurotrophin production and so help to protect.lctglobal.jp/en/).to late-stage myeloid progenitor cells.9 million in 3 option years. Life Cell is poised to further develop its second xeno-cell therapy product NTCELL® aimed for treatment of Parkinson’s disease. repair and possibly regenerate brain and nerve tissue. Cellerant will receive up to $80 million in the 2-year base period of performance and up to an additional US$89. » Xeno-cell therapy attracting investments Australia/New Zealand-based Life Cell Technologies (www. Choroid plexus cells secrete neurotrophic factors vital to the health and survival of brain tissue.

After gaining experience in pathology. and completed her post-doctoral training in Molecular Neurogenetics at Massachusetts General Hospital.. One of the reasons the gene therapy clinical trials failed was that the cells implanted did not move away from the injection sites. Here. and 2008 ASGCT Outstanding New Investigator Award. Harvard Medical School.12. (2012) 7(6 Suppl. I was in the right place at the right time. In 2010. gene therapy and biotechnology. We asked ourselves. Med. he brought neural stem cells to Dr Breakefield’s brain tumor laboratory.85 © 2012 Future Medicine Ltd Regen. We needed a delivery vehicle that could migrate to target the residual tumor sites and invading cells. She recently founded a clinical-stage biopharmaceutical company. to support clinical development of neural stem cell-mediated cancer therapies. she joined City of Hope (COH) in 2003 to head a translational research laboratory focused on therapeutic stem cell applications for invasive and metastatic solid tumors. This Phase I study is ongoing at COH. USA). she received US FDA approval for a first-in-human clinical trial for neural stem cell-mediated therapy for high-grade glioma patients. such as stroke. Dr Evan Snyder had shown that neural stem cells (NSCs) could localize to injury in the brain.). Q How did you first become involved in stem cell research? I was working in the neurogenetics laboratory of Dr Xandra Breakefield at Massachusetts General Hospital. demonstrating that Karen Aboody received her MD at Mount Sinai School of Medicine. In 2010. 64–66 ISSN 1746-0751 . and why all biomedical researchers need to know what it takes to make the transition if they want the best chance of seeing their discoveries used to help patients. would they migrate to sites of cancer as well? That led to our breakthrough studies. COMMERCIALIZATION & COLLABORATION Interview Researchers and the translational reality Interview with Karen Aboody Karen Aboody has first-hand experience of taking a potential therapy from the laboratory into clinical trials. published in Proceedings of the National Academy of Sciences in 2000. She was one of the leaders in gene therapy so I got involved in running the preclinical HSV-TK gene therapy trials for glioma – the most aggressive type of brain tumors. so they could not deliver their therapeutic payload to all of the tumor cells that were invading into normal brain. TheraBiologics Inc.2217/RME. 64 10. if NSCs could migrate to sites of injury. Harvard Medical School in Boston (MA. supported by NCI/NIH funding. Honors include the 2000 AANS Young Investigator Award. she received an US$18 million California Institute of Regenerative Medicine Disease Team Award to develop a second-generation enzyme/prodrug stem cell-mediated brain tumor therapy for clinical trials that may also have applications for other metastatic cancers.INDUSTRY. and took advantage of this opportunity to study these stem cells in more detail. They just treated the area in the immediate vicinity of the injection site. When his best friend got diagnosed with a glioma. she shares with us the challenges and rewards of going from bench to bedside.

Researchers & the translational reality NSCs had an inherent ability to target cancer sites in the brain and invasive tumor cells – even when they were injected at a distance from the tumor [1] . we began to consider the best payloads the NSCs could deliver to the tumor cells – to localize the chemotherapy selectively to the tumor sites and minimize toxicity to normal tissues. In addition to safety and efficacy studies. including glioma. reducing chemotherapy-associated side effects. surgery and radiation. Once this was clearly demonstrated.futuremedicine. in essence targeting the therapy selectively to the tumor cells. to understand the mechanisms involved in the tumor-targeting ability of the NSCs. lung cancer and melanoma – in addition to glioma patients. The patient is then treated for 7 days with the prodrug. These patients have failed chemotherapy. We expect the NSCs to migrate through brain tissue and localize to residual tumor sites and invasive tumor cells. Once the Phase I study is completed we hope to give multiple rounds of treatment and open the trial to patients with secondary brain tumors – patients with brain metastases from primary breast cancer. breast carcinoma and colon cancer. When the drug reaches the brain.: what led you to found the company? I founded the company [101] last year to ensure funding for clinical development of this therapy. City of Hope initiated a Phase I clinical trial using NSCs to deliver targeted chemotherapy to patients with brain tumors. This would be a multidose trial for patients with recurrent high-grade glioma as well as solid tumor brain metastases. in 2010 we also received a US$18 million Disease Team Award from the California Institute of Regenerative Medicine to develop a second generation of therapeutic NSCs to clinical trial by 2015. We are testing four escalating doses with a total of up to 20 patients. This targeted therapy should greatly reduce toxicity to normal tissues and chemotherapy-associated adverse side effects. Importantly. Our NSCs are engineered to produce an enzyme (cytosine deaminase) that will activate a prodrug (5-fluorocytosine) to an active chemotherapeutic agent (5-fluorouracil). the stem cells will activate it to the chemotherapeutic agent locally at the tumor site. If www. The same NSCs in the current Phase I trial are further modified to deliver a carboxylesterase enzyme that will convert irinotecan to its activated form SN-38 – a chemotherapy agent that is 1000-times more potent for tumor killing than irinotecan alone. Tell us a bit more about TheraBiologics Inc. ultimately. What is the main focus of your research at City of Hope? NSC-mediated cancer therapy focused on translation from the bench to the clinic. In November 2010. and keep it moving forward. ” 65 . This strategy may have potential applications for other types of cancers in addition to brain tumors [2] . This first-in-human stem cell-mediated cancer trial was designed as a safety/ feasibility study to treat recurrent highgrade glioma patients.com “ Our aim is to scale‑up manufacture and production of our cells and open a multicenter Phase II trial. industry must step in to cover the huge costs of Phase II–III clinical trials. we are also trying to determine the specific signals involved in the stem cell–tumor tropism. medulloblastoma and solid tumor metastases to the brain. as hundreds of millions of dollars are needed to move a therapeutic technology to commercial product. I learned that. only one round of NSCs + prodrug treatment is being conducted. Our lead studies are using the NSCs to deliver various therapeutic payloads to brain tumors. and have a grim prognosis of less than 6 months survival. Currently. Tell us a bit more about the trial design and end points. including neuroblastoma. future science group The stem cells are injected into the brain tumor site at the time of surgical resection or biopsy. We are also investigating intravenous administration of NSCs to treat metastatic cancers.

I had to face the true facts – money matters. Rainov NG et al. www. As idealistic as I was. and gain a new perspective – to start thinking how their discoveries can be applied toward disease treatment and prevention. clinicians.therabiologics. Support and attention need to be given to translational scientists. What do you see as the greatest challenges for basic scientists entering the translational arena? To team up with translational and clinical researchers. We are breaking new ground with potential stem cell treatments. Najbauer J. 12846–12851 (2000). the technology is ‘dead on the vine’ no matter how promising it may be. Translational research bridges the two and involves a team effort. Others will soon join you. Aboody KS. City of Hope supported me with a team of colleagues. I believe it is important for scientists to think even beyond clinical trials. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Niazi N. we want to help the patients. What are the key milestones for the company over the next 5 years? Our aim is to scale-up manufacture and production of our cells and open a multicenter Phase II trial. Stem and progenitor cell-mediated tumor selective gene therapy (review). No writing assistance was utilized in the production of this manuscript. Sci. These trials are planned to start in 2015. My advice would be: do not give up – do not get discouraged by negative comments from others. The more understanding we have of the disease processes. including researchers.Aboody one cannot get funding for this clinical development. Brown A. Researchers and clinicians are not trained for translational research. Capela A. What was the best advice you were given and what advice would you give other scientists making this transition? When I first came to City of Hope. Ultimately. I recently wrote an article with Dr Sally Temple that highlights the process of translating stem cell therapies to the clinic. my Chair asked me.com 66 Regen. manufacturing and regulatory experts to reach my goals. which is an ideal environment for translating research from the bench to the bedside. Temple S. Clinicians want what works to treat their patients. it is a process you have to learn. 15. Proc Natl Acad. Gene Ther. The process involves a collaborative team effort. Stern JH. trust your gut. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. and resources available [3] . This would be a multidose trial for patients with recurrent high-grade glioma as well as solid tumor brain metastases. Translating stem cell studies to the clinic for CNS repair: current state of the art and the need for a Rosetta Stone. Med. for which there is no precedent. GMP manufacture and regulatory affairs. who form the bridge between basic research and clinical research. I encourage my post docs to get some industry experience. USA 97(23). Basic scientists want to understand the how and why of the disease process. 739–752 (2008). New concepts will always draw criticism and skepticism. How important is it for biomedical scientists to be aware of the potential to translate their work? It is extremely important to examine our scientific discoveries from the laboratory and determine how they might be applied for clinical use. a clinical-stage biopharmaceutical company that she founded in 2011 to advance stem cell-mediated cancer therapies. Danks MK. Financial & competing interests disclosure K Aboody is an officer and founder and director of TheraBiologics Inc.) future science group . including the funding and regulatory obstacles. 3 „„ Website 101 Therabiologics 2 Aboody K. “What is your vision? If you could do anything you wanted here – what would you do?” That gave me the space to think big – I wanted to move my research to clinical trial but I did not know how.. Keep your eye on your goals. Neuron 70(4). We also plan to raise enough capital to fund upcoming Phase I trials using further modified NSCs to deliver two different therapeutic payloads. clinicians. and just keep moving forward. (2012) 7(6 Suppl. References 1 Aboody KS. the more potential targets are elucidated for treatment strategies to be developed and applied. 597–613 (2011).

Science Signaling and Science Translational Medicine. wherever you go. AAAS members can access full text articles from Science. How and Why DATE: Sep 21. Too DATE: Sep 21. 7:43am LOCATION: University Faculty Lounge ARTICLE: The Visual Impact of Gossip DATE: Sep 21. 1:13pm LOCATION: Bed ARTICLE: Consciousness: What. Plus.LOCATION: Jackson Park Health Club ARTICLE: An Electronic Second Skin DATE: Sep 21.org/ipad for details. Visit iTunes App StoreSM or content.aaas. 9:21pm LOCATION: Gyro King ARTICLE: Cavemen Craved Carbs. Read abstracts. 4:22pm LOCATION: Hemlock Bar ARTICLE: Quantum Simulation of Frustrated Classical Magnetism in Triangular Optical Lattices DATE: Sep 21. 10:56pm A new way to look at science The new Science Reader App for iPad® from AAAS puts Science in your hands. career advice. and highlights from our newest journals. .


Interview The Regenerative Medicine Coalition

Interview with Frank-Roman Lauter


Frank-Roman Lauter, Secretary General of the recently launched Regenerative Medicine Coalition, explains how the coalition was formed and what they hope to achieve. Frank-Roman Lauter has served as Secretary General of the Regenerative Medicine Coalition since 2012, and as Head of Business Development at Berlin-Brandenburg Center for Regenerative Therapies since 2007. Frank-Roman Lauter’s interest is the organization of academic infrastructures to promote efficient translation of research findings into new therapies. He co-organizes joined strategy development for regenerative medicine clusters from seven European countries (FP7-EU Project) and has initiated cooperation between the California Institute for Regenerative Medicine and the German Federal Ministry for Education & Research, resulting in a joined funding program. Recently, he cofounded the international consortium of Regenerative Medicine translational centers (RMC; www.the-rmc.org). Trained as a molecular biologist at the MaxPlanck Institute in Berlin-Dahlem and at Stanford, he has 16 years of experience as an entrepreneur and life science manager in Germany and the USA.

Briefly, what is the Regenerative Medicine Coalition? The Regenerative Medicine Coalition (RMC) is a working network, a consortium of leading international translation centers in the field of regenerative medicine. Our mission is to accelerate therapy development in regenerative medicine. How did you get involved and what is your role within the coalition?

between academia and industry. During the workshop we decided that it would be beneficial to improve communication and collaboration between the various translational centers in our field on an international level, avoiding the repetition of mistakes, sharing knowledge and infrastructure, helping to raise the profile of our member translational centers and collaborating on joint projects.

In February last year, together with Chris Mason (UCL, London, UK) and Greg Bonfiglio (Proteus Venture Partners, CA, USA), I organized an executive workshop in Berlin on collaborative technology development in the field of regenerative medicine. We invited about 30  key opinion leaders from industry, public/ private funding organizations, academia and translational centers, to discuss how to achieve more efficient (and more cost efficient) product development in the area of regenerative medicine. What kind of environment is needed? What kind of infrastructure? A special interdisciplinary infrastructure is needed to boost the development of new therapies in our field. Existing translational centers provide this infrastructure that bridge ‘bench to bedside’. They are ideal interfaces
10.2217/RME.12.86 © 2012 Future Medicine Ltd

[Regenerative Medicine Coalition’s] mission is to accelerate therapy development in regenerative medicine.

Together with the heads of a number of translational centers, we cofounded RMC. I am serving as the first Secretary General of the coalition at our headquarters in Berlin (Germany). I am responsible for the operational business of the coalition. What are the key aims of the coalition over the next few years? First, we want to establish an efficient collaboration infrastructure between the member translation centers – we want to establish a fixed communication
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By facilitating the identification and execution of joint projects and providing due diligence services for those joint projects early on, the RMC will help to de-risk projects [and] lower the hurdle for public and private investors to participate in regenerative medicine therapy development.
schedule, with monthly video conferences, biannual workshops and meetings. We will also be looking for other translational centers that complement the existing co-members, in terms of expertise and territory. Currently, we have seven members from translational centers who make up our core membership but we would like to expand that to 12 by the end of this year. For example, so far we have no Asian members in our coalition so that is something we would like to rectify. Second, we are working on compiling and prioritizing technological bottlenecks that are holding off the field. In our consortium, we plan to jointly address those bottlenecks and provide new technological solutions. In addition, the RMC plans to engage in joint therapy development projects. We want to organize additional public and private funding to execute those joint projects and become a major contact point for industry wanting to collaborate on projects for regenerative medicine. Within our translational centers we are able to execute projects from a blank piece of paper through to proof-of-concept Phase  I/IIa clinical trials. The RMC also plans to raise additional money that will allow us to invest in validation studies, bridging the ‘valley of death’ and bringing projects to a point where they become very attractive for investors. What will be the coalition’s role in relation to other regenerative medicine organizations (e.g., Alliance for Regenerative Medicine)? The RMC is focused on the execution of joint technology development and its core is a working network of translational centers in regenerative medicine. Organizations such as the Alliance for Regenerative Medicine mainly focus on issues of regulation, reimbursement and policy. All of those are very important to create a receptive environment for new regenerative medicine solutions, allowing those new therapies to reach patients quickly and safely. So I believe that the RMC and Alliance for Regenerative Medicine will complement each other nicely. What will the benefits be for those joining the coalition? There will be three types of members: core members, industry members and associated members. The main benefit for the core members is an opportunity for efficient technology development. It also gives them access to larger expertise pools for knowledge and ideas sharing, and provides the critical mass to realize joint projects. Some major projects might not be achievable by one translational center alone, but if two or three join forces, much bigger projects become possible. For the industry members, the benefit is an opportunity to have input into research and development directions that go into translation and on standards that have to be fulfilled. They will have a first look at new technologies, and be able to access translational infrastructure and resources.

For associate members, public and private funding organizations, it is an opportunity to support RMC in economic development. Projects from translational centers will eventually be licensed to industry or spin-off into start-up companies, so they will create new economic growth. Investors will have access to an international pool of leading experts in the field. By facilitating the identification and execution of joint projects and providing due diligence services for those joint projects early on, the RMC will help de-risk projects. The RMC will help to lower the hurdle for public and private investors to participate in regenerative medicine therapy development. What will be the process for organizations wanting to join the coalition? We welcome other translational centers as well as industry and public/private funding organizations to join the RMC. Shortly, we will post RMC’s future membership policy on our website (www.the-rmc.org) making it easy for additional members to join our consortium.

Financial & competing interests disclosure F-R Lauter is serving as the Secretary General for the RMC. He does not receive any salary for this function in the RMC. He is employed by the Helmholtz-Zentrum Geesthacht, Centre for Biomaterial Development and works at the Berlin-Brandennburg Center for Regenerative Therapies at Ca mpus Cha rité Vichow, Augustenburger Platz 1, 13353 Berlin, Germany. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. ­


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future science group

With all our awards. Diseases or conditions covered include heart/blood disease. dubbed ‘Disease Team’ awards. CIRM initiated the Collaborative Funding Program. a host of neurological disorders. we have emphasized this notion and are gratified to see so many teams that we have funded working together in the midst of exciting scientific advances on both a national and even international level. but particularly the largest ones.12. different counterparties have different amounts of money to fund such things as stem cell research. the California Institute for Regenerative Medicine (CIRM) has set out to fund projects along the product development spectrum. we cannot fund scientists outside California. These funding disparities reflect both a given counter party’s emphasis on the research itself. both within and outside California. While the concept here is simple. There were 14 awards in all. USA. the name of the game in stem cell science is collaboration. cancer. 38 currently incurable diseases and conditions and 23 different academic institutions or biotechnology companies.INDUSTRY. Under Proposition 71. (2012) 7(6 Suppl. Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University is teaming up with Paresh Vyas of the Weatherall Institute of Molecular Medicine at Oxford University in the UK to generate a monoclonal antibody that destroys leukemia stem cells. Chairman. the logistics may not be. The concept here was simple. team members come from different institutions or companies within California. Some agreements are finalized in a matter of weeks or months. diabetes. skin disease and liver disease. That team and project would be subject to the same rigorous peer review by our Grants Working Group as all other grants in that round. with many projects on their way to the clinic. All Collaborative Funding Agreements take time to negotiate. 71–72 71 . bone/cartilage conditions. USA is partnering with Tak Wah Mak. Since inception. In many instances. These awards have produced exciting interim results. notwithstanding everyone’s interest in getting them done. These awards total more than US$590 million. Other teams include members from outside California (both domestic and international). San Francisco. in response to increasing interest in multinational stem cell research teams. Under the terms of the Collaborative Funding Program. CA 94107. And Dennis Slamon. COMMERCIALIZATION & COLLABORATION Commentary Collaborations in stem cell science Jonathan Thomas* Increasingly. we have funded 75 awards.2217/RME. CIRM would pick up the costs for the California scientist(s) in the team while the other sponsoring entity would pick up the costs for its scientific team. CA. blindness. can frequently achieve more by working together than they can by going it alone. From the outset. In the latter portions of that pipeline. Med. This article highlights CIRM’s collaborative strategies and brings you up to date on the extent of our program in this regard. These are our so-called ‘Collaborative Funding Partners’. from basic research through early translation and preclinical work to Phase I/II clinical trials.net 10.67 © 2012 Future Medicine Ltd Regen. A couple of those awards are illustrative of collaboration in action. More on them later. We at the California Institute for Regenerative Medicine (CIRM) feel strongly that scientists from academia and industry. Each counter party has its own political and regulatory frameworks to deal with. bring together scientists with a wide variety of skills and areas of expertise to tackle the target disease or condition in question. The California Institute for Regenerative Medicine. jthomas@saybrook. however. with more likely through new awards to be made in the coming months. totaling $225 million from CIRM and another $43 million from two of our international partners. These awards. a scientist from outside California can join with an in-state scientist to submit a grant in response to a particular Request for Applications issued by CIRM. work with such scientists if their part of the cost is picked up by their sponsoring jurisdiction. Beginning in 2008. HIV/AIDS. to date. of the Jonsson Comprehensive Cancer Center at UCLA.). 210 King Street. Others have taken many months or years. of the University Health Network in Canada to develop drugs that destroy the cancer stem cells in solid tumors. Still others are yet to be finalized and remain works in progress. We can. among others. Our first round of Disease Teams were awarded in October 2009. Separate from the logistics. collaboration is key. This takes many forms. If that project is ultimately recommended for funding and approved as such by our Board. Irving Weissman. preference given to academia over industry (or vice versa) ISSN 1746-0751 *Author for correspondence: Jonathan Thomas.

it leads to leveraging funds from multiple 72 jurisdictions to conduct critical research. As of press time.’ This advantage directly results in the acceleration of inventions and discoveries. it facilitates the convergence of ethical and regulatory standards in the field. I wanted to make a few specific points on the increasing need for collaboration between academia and industry. CIRM places great emphasis on its collaborative funding program. Both logistics and funding factor heavily into the Collaborative Funding negotiations. Fifth. Finally. We will continue to emphasize this approach and expect the citizens of California and the world to reap the benefits for many years to come. 13 are countries: Argentina. As we see it. No writing assistance was utilized in the production of this manuscript. a number of these potential alliances are under discussion. ­ future science group . both within the USA and in other countries. in a goal explicitly set forth by Proposition 71. USA. Having said all of the above. France. shared research equipment. it promotes ‘best practices’ among funders. We will continue to emphasize this approach and expect the citizens of California and the world to reap the benefits for many years to come. if you will. allowing funders to understand shared priorities and to minimize duplicative expenditures. We believe that this approach is going to pay dividends. stock ownership or options. First. To ultimately succeed. Spain. Japan. Such collaboration benefits both big pharma.) “ ” Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. shared data sets. expert testimony. eliminating the need to ‘reinvent the wheel. we now have 20 partners. and Andalucia (Spain). Several are foundations: New York Stem Cell Foundation. Of those. or royalties. A big issue with all of these awards (be they to academics or biotechnology companies) is how will the work in question be funded down the line when our (or other early-stage) money has been spent? This is a pressing problem as the later stage funders (venture capital. our projects need a seamless transition to later stage funding. an increasing number of basic biology grants have collaborative funding partners as well. etc. (2012) 7(6 Suppl. Australia. Sixth. it promotes the efficient use of resources such as shared cell lines. who get relationships with deep pockets that can ultimately fund the commercialization of their products should things play out through the early clinical trial process. This includes employment.Thomas and/or the economic realities of the times. scientists can work with their most advanced peers from around the world. The balance are states. We spend a lot of time pondering this need and have begun a series of dialogues with big pharma with the goal of driving earlier stage strategic alliances between big pharma and our awardees. Victoria (Australia). it allows researchers to take advantage of discoveries from other jurisdictions. accelerating their progress. big pharma) are not typically getting into the game these days till a funded project has produced Phase II results. India. Taking stock of the collaborative projects funded to date. Will collaborative funding ultimately yield ‘better’ science? Is there enough experience in the stem cell field to support that conclusion? What is the best way to measure? Would the field achieve the same ultimate results without collaborative teams? Does the availability of collaborative funding skew the research that gets pursued? Finally. such as Maryland. China. CIRM has the privilege of funding research normally stalled in the so-called ‘Valley of Death’ – that unfunded stage of the research continuum between basic science and Regen. grants or patents received or pending. shared assays. over $148 million contributed to that work has come from the collaborative funding partners themselves. the ALS Foundation and the Muscular Dystrophy Association. honoraria. Before concluding. A classic win-win. These collaborations have led to 26 ongoing research projects with several more likely to be funded later this year. …we believe that collaboration on all fronts is a good thing. which gets an early stage look at potential products to fill their pipeline. Canada. we believe that collaboration on all fronts is a good thing. Beginning with its first collaborations with Canada and the Australian state of Victoria in 2008. consultancies. In conclusion. Germany. a number of questions remain. Third. Fourth. It allows CIRM and its counter parties to share the cost/burden of their respective research contributions. Through funding provided by Proposition 71. and early researchers. there are a host of benefits that arise from these collaborative efforts. We will continue to facilitate these discussions and are hopeful that a number of these relationships will bear fruit. early-stage clinical trials. Scotland. Brazil. Med. Juvenile Diabetes Research Foundation. Second. I should note that while most of the funded collaborations are with our larger awards. mitigating the requirement that all funded work must take place in CA. can regulatory inconsistencies be effectively managed? What happens when regulatory requirements diverge or conflict? Will these inconsistencies ultimately doom the effort? These and other questions will play out over time. the UK and USA through the NIH. it supports scientists in nascent or early-stage research communities to work with scientists in more advanced arenas.

com .key to stem cell biology Easy single-cell passaging Clonal ES cell cultures with high efficiency! 1.000 years of employment generated through 2014 38 without rock of human PS cells diseases could be impacted $286 million Defined and xeno-free monolayer stem cell cultivation in new CA tax revenue Visit us in the exhibit hall and at biolamina.200+ discoveries published 38.CIRM RESULTS 75 12 500+ grants awarded new institutes built projects developing therapies Human recombinant laminins .

Beckman Research Institute at City of Hope. and innovative industry leaders toward a common driving goal to move scientific discovery to clinical application. USA *Author for correspondence: Mardi de Veuve Alexis. Karl-Henrik Grinnemo & Richard Jove The International Translational Regenerative Medicine Center. including molecularbased therapies and biologics that target devastating and debilitating diseases. personalized medicine and innovative therapeutic models that target globally pervasive chronic and life-threatening diseases. such as cancer. has the largest academic GMP facility and advanced drug discovery capability. the ITRC model is project-based. The ITRC’s principal translational focus is on stem cell technology and innovative regenerative clinical applications. between the research groups at Beckman Research Institute at City of Hope (BRI/COH) and among future collaborators and partners (Box 1). CA. The International Translational Regenerative Medicine Center (ITRC. In a world of rapid communication through the Internet and ISSN 1746-0751 74 10. USA Key elements „„ Information exchange Translational science is driving a growing need to share information and databases. including stem cell lines for research. an organizing sponsor of the World Stem Cell Summit 2012. databases and other registries. Unique from. Sweden Richard Jove. Sweden) and Beckman Research Institute at City of Hope (CA. (2012) 7(6 Suppl. technology exchange and collaboration. As the world faces enormous health challenges in the 21st century that are compounded by an unprecedented aging population.INDUSTRY. USA) with a mission to facilitate the acceleration of translational research and medicine on a global scale. diabetes and neurodegenerative disorders. The Beckman Research Institute/City of Hope is ranked among the leading NIH-designated comprehensive cancer research and treatment institutions in the USA.72 © 2012 Future Medicine Ltd Regen. Molecular Medicine and Translational Science. is a global initiative established in 2011 by founding partners Karolinska Institutet (Stockholm. Karolinska Institutet.). home of the Nobel Prize in Medicine or Physiology. The ITRC fills an unmet need to develop a global model that raises the bar on international standards of excellence in biomedical research and coalesces international academic centers of excellence. intellectual property rights. is one of the most prestigious medical research institutions in the world. Med. and is a pioneer in diabetes research and treatment. Stockholm. This project-based approach promotes accessibility. “ ” Karl-Henrik Grinnemo. Duarte. ITRC has begun to develop and exemplify the highest standards of ethical and clinical protocols in research and clinical applications by facilitating the coordination of research within and among the research groups in each of four regenerative networks at Karolinska Institutet (KI). the ITRC addresses a growing urgency to expedite the pace of translational research to the point of patient care. CA.2217/RME. and mutually derived discoveries and knowledge that lead to better treatments and cures of major diseases. Beckman Research Institute at City of Hope. coalesce and build a network of prominent scientists and clinicians from distinguished research institutions and teaching hospitals worldwide. COMMERCIALIZATION & COLLABORATION Organization profile The International Translational Regenerative Medicine Center Mardi de Veuve Alexis*. centers for stem cell and regenerative medicine.12. International Translational Regenerative Medicine Center. innovative therapeutics development and human clinical trials. talented scientists and physicians. Partner institutions maintain their autonomy and uniqueness while benefiting from the resources and synergy provided by the ITRC. ITRC also facilitates technical assistance between and among partnering institutions and government entities. Clinical Research and Regenerative Medicine. providing an international hub and infrastructure to support. Karolinska Institutet. pronounced ‘i-track’) responds to a major paradigm shift in scientific research and translational medicine that has evolved in recent years with the promise of stem cell research. animal research facilities. yet complementary to. numerous biomedical consortia that have been initiated in recent years. 74–75 . The International Translational Regenerative Medicine Center’s principal translational focus is on stem cell technology and innovative regenerative clinical applications… The ITRC platform features state-ofthe-art GMP facilities.

Partnering institutions identified and invited to join ITRC on the basis of their internationally recognized expertise and leadership in the field of translational and regenerative medicine. A distinguished Advisory Board comprises prominent local and international leaders. the ITRC facilitates dialogue. grant opportunities and clinical trials to develop state-of-the-art treatments. academic and industry partners. MTA. Most of the scientific and clinical research will occur among members of each respective Task Force. Opportunities to secure funding and grants through both governmental institutions or through private sources in the USA. diabetes and metabolic disorders. program execution. In particular. www. advanced communication technologies that facilitate the exchange of information. universally accessible bioinformatics is also accommodated through the ITRC.The International Translational Regenerative Medicine Center Box 1. expert testimony. collaborators and interested consumers. including pharmaceutical and biotechnology companies.ITRCmed. regulatory support resources. The ITRC addresses diseases such as cancer. philanthropic resources and government agencies. outside principal investigators.net will present regular news and information complemented by traditional print communications for partners. management and interface between and among partnering institutions and collaborators. The ITRC is administered from both KI and BRI/COH. technology transfer. Meetings and symposia alternating between KI in Sweden and BRI/ COH in California are held quarterly and biannually to present ITRC projects and research outcomes. future science group Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. The Operations Team oversees GMP. overseeing ITRC budget and operations. providing coordination. and program delivery among partners and collaborators. prioritizes research collaborations. media. coordination of research activities. These partnering institutions will be held to strict standards of excellence and core ethical values that define and brand ITRC. neurodegenerative and heart disease through human trials utilizing stem cell technology and transplantation. meeting agendas and symposia. regulatory and legal issues. respectively and collectively. Through its interactive network.. potential cures and a better quality of life for patients suffering with globally pervasive debilitating diseases. administrative and fiduciary oversight. consultancies. EU. The ITRC provides partnering institutions a network of expertise to facilitate and complement collaboration among leading researchers (e. Sweden and other countries will also be facilitated through the ITRC infrastructure. The science: pilot projects. and nanotechnology.futuremedicine. KI and BRI/COH oversee and facilitate project funding opportunities and management through the ITRC’s Executive Council.com which has scientific. grants or patents received or pending. Working Task Forces are integral for each project to facilitate collaboration among principal investigators and others within the scope of specific project goals and objectives. the ITRC draws upon specific expertise and knowledge of leading researchers and clinicians. molecular diagnostics and treatments. honoraria.net The ITRC’s homepage at ITRCmed. Partnerships with industry. including international research institutions and potential partners. evaluates and determines new international. No writing assistance was utilized in the production of this manuscript. „„ Collaboration & enabling technologies The ITRC provides the framework for multidisciplinary collaboration among investigators to efficiently hasten the translation of research findings in basic research to medical practice for improved treatment protocols and health outcomes. will support commercialization. The initial research project areas underway between Karolinska Institutet and Beckman Research Institute at City of Hope and other institutional collaborators include: ƒƒ Parkinson’s and human embryonic stem cell-derived midbrain dopamine neurons ƒƒ Cardiomyocytes and cardiac progenitor cells as strategies for regeneration ƒƒ Leukemia stem cells to evaluate sirtuin inhibitors ƒƒ Targeting proliferating cell nuclear antigen in cancer cells ƒƒ Treating myeloma with natural killer cells and small molecules ƒƒ Early xeno-free clinical-grade human embryonic stem cell lines Project abstracts are available upon request or at www. compliance. ­ 75 . the formation of disease-focused research teams) to strengthen the potential for funding. and engages in problem-solving on ITRC-related issues. audits and government grants.g. or royalties. Technologies and tools that enable research to clinical practice with GMP. patient advocates. joint research initiatives. stock ownership or options. Partnering institutions shall be defined. This includes employment. and business expertise leading to increased research productivity and commercialization will be developed and shared through the ITRC infrastructure. „„ Government regulatory & research funding support The ITRC offers technical support to help partnering institutions through the process of government approvals. researchers from the various KI/BRI-COH regenerative networks and relevant research departments of both founding institutions and future partners.

for advertising opportunities. DAILY MONTHLY ON DEMAND Check out our new targeted digital supplement.LaboratoryEquipment. LabOutlook. liz. and other laboratory professionals turn to LABORATORY EQUIPMENT quickly and easily in the convenient formats that suit their informational needs. at 631-241-6161. engineers.” Visit www.vickers@advantagmedia. Publisher.com. .More Insight The Trusted Information Source for Laboratory Professionals More lab managers. which is dedicated to “building the lab of the future…today. scientists.com to subscribe to our magazines and newsletters Contact Liz Vickers.

xxx–77 ISSN 1746-0751 77 . (2011) 6(5 Suppl. collaborations and consortia: the International Stem Cell Forum and its role in shaping global governance and policy Rosario Isasi Cell standardization: purity and potency Belinda J Wagner Opinions Autologous cell therapies: challenges in US FDA regulation Todd N McAllister.2217/RME. Tim Mayleben & Gil Van Bokkelen Perspective Pay-to-participate funding schemes in human cell and tissue clinical studies Douglas Sipp 10. David Audley & Nicolas L’Heureux Autologous cell therapies: the importance of regulatory oversight Michael Werner. REGULATION & ETHICS CommentarIEs Regulation.ADVOCACY & EDUCATION Article type POLICY.XX.XX © 2011 Future Medicine Ltd Regen.). Med. manufacturing and building industry consensus Robert Deans Alliances.

). using staged clinical trials. Cleveland. therapeutic manu­ facturers.POLICY. and certainly not used outside of autologous or patient-matching restrictions.98 © 2012 Future Medicine Ltd Regen. In fact this open development practice led to effective therapies becoming standard of care in the transplant setting.12. which evolved to the International Society for Stem Cell Therapy (ISCT) and creation of the Foundation for the Accreditation of Cell Therapy. in conjunction with hematology societies. Med. and finally patient advocacy groups. but were tool and service driven. and investment milestones were driven by core manufacturing and preclinical data leading to Phase I clinical entry. In fact. driven by refinement of stem cell isolation and characterization technology and practiced in a tissue transplant paradigm. only in the past year has the US FDA acted to have cord blood products regulated under the Investigational New Drug Application. A consequence of the pharma and healthcare sector waiting on the sidelines for proof of clinical concept was that these emerging technologies did not benefit from experienced development eyes.. This industry was regulated through medical devices and reagent CE marking rather than clinical development towards Biologics License Approval approval *Author for correspondence: Robert Deans. Parallels are often drawn between regenerative medicine technologies and the adoption of antibody biologics. many of the critical development criteria such as scalability. Practicing this transplant business model had important ramifications for product acceptance into standard of care. Accreditation standards and harmonized product characterization standards were developed in conjunction with industry and provided the clinician with greater confidence in product conformation. successful clinical development and recruitment of capital sufficient to reach market approval is measured as an industry platform. but cycling out following these early value creation milestones. 78–81 . pharma and the capital markers. with initial cycles of optimism leading to a financial ‘valley of death’ before validated technologies reach the market and establish the manufacturing and business models sufficient to derisk investment and grow the market opportunity. cost of goods sold (COGS) and reimbursement price points were only superficially addressed. Investors were not in a financial cycle linked to product approval and sales. It is important to realize that the business models developed in this paradigm did not capitalize on intellectual property around cell composition of matter. The ‘product’ was in fact a process centered around individual donor tissues and cell processing technology. ISSN 1746-0751 Development principles driven by hematopoietic therapies Regenerative medicine cell therapies were birthed from the hematopoietic stem cell transplant space. failure and achievement by individual companies are shared by all in the context of access to enthusiastic capital markets and codevelopment partnerships. was able to run comparative clinical studies between competing technology approaches with public dissemination of product quality and patient response. The practicing physician. manufacturing and building industry consensus Robert Deans* As has been true with many emerging technologies. it behooves us as an industry to challenge the complexities of cell-based therapy and act strategically to build and communicate solutions to those stakeholders on the commercialization path: the translational physicians. Cell therapeutics for regenerative medicine were in their infancy 15 years ago.2217/RME. While this may offer some solace. Risk. Hematopoietic and blood cells were generally not expanded prior to therapeutic use. held by clinical product distributors [101] . 3201 Carnegie Avenue. Physician networks were able to coordinate best practices and accreditation standards through organizations such as International Society Hematology and Graft Engineering (see Table  1). As a consequence. USA 78 10. OH 44115-2634. Athersys Inc. (2012) 7(6 Suppl. REGULATION & ETHICS Commentary Regulation. regulatory bodies. Critical thinking towards manufacturing scalability and costs has come late into this industry and has become a critical validation and competitive technology fulcrum.

One interesting facet integral to reimbursement discussion is the use of a common therapeutic product to treat a variety of indications. A consensus was developed and harmonized for MSC lot release criteria targeting: ƒƒ Sterility.com .futuremedicine. the low immunogenicity and active immunodulatory properties of this class of cells created a new paradigm for clinical practice. First. and had indirect benefits as well. Initiated by the Osiris/Genzyme partnership. The initial practice for MSC therapy was carried out in institutional stem cell processing labs. The bioprocessing industry has not aggressively entered the scaled cell manufacturing space due to uncertainty for clinical proof of concept and the absence of product approval and validation of economic business models. dedicated manufacturing capacity was built around closed 2D minibioreactors exemplified by Corning Life Sciences ten-layer cell factories. most therapeutic manufacturers have stayed in a primarily 2D manufacturing mode with limited output in clinical production campaigns. Clinical indications range from life-sparing treatment of graft versus disease. the Pluristem/United Therapeutics deal. purit y and viabilit y determined by flow cytometry. ƒƒ Biological potency. the ex vivo expansion potential of this class of cells created future science group Table 1. and fostered important codevelopment partnerships based on this model being familiar to pharma and healthcare providers. [102] [102] [103] [104] [105] Transitioned to ISCT and FACT [106] [107] a scalable manufacturing model with many attractive features. Acronym AAT ARM EPSRC FACT ISCT ISHAGE LRMN SBE Society Alliance for Advanced Therapeutics Alliance for Regenerative Medicine Engineering and Physical Sciences Research Council Foundation for the Accreditation of Cell Therapy International Society for Cell Therapy International Society Hematology and Graft Engineering London Regenerative Medicine Network Society for Biological Engineering Ref.and late-phase clinical testing was a key advance for the industry. 79 Maturing manufacturing in the MSC sector The development path for this class of products has been rocky. The hesitancy in MSC clinical development has had impact on implementation of next-generation manufacturing technologies. proof of biological mechanism seems to be generally accepted. manufacturing & building industry consensus The sea change with mesenchymal stromal cells The regenerative medicine landscape has been changed significantly by scientific advances in stem and progenitor cell technologies. Demonstration for manufacturing scale to meet mid. Notably. Cell therapy and regenerative medicine organizations. and sufficient capital is in play that the MSC industry is now turning to face important questions around COGS and reimbursement. a decision with striking implications for company assessment of lead indication and market breadth. ƒƒ Cytogenetic stability. shifting from a patient-designated transplant product to a universal donor product that could be manufactured and distributed as a biologic without patient matching. As a consequence. The combination of universal donor properties and scalable manufacturing reinforced the biologics paradigm for this class of cells. a close relationship was created between industry and the FDA and European Regulatory agencies to cross-educate and develop a template for regulating this class of cells. Standards for phenotypic markers and biological potency were reinforced by society position papers crafted by academic and industry thought leaders [1. However. MSC technologies have had profound influence on the regenerative medicine market based upon key biological properties. with ISCT playing a major role at early stages. and also represented a product class defined by cellular composition of matter. the development of mesenchymal stromal cell (MSC) technologies in the mid-1990s was the first foray for the Investigational New Drug Applicationdriven nonblood cell therapeutics. With industry engagement in this space manufacturing concepts evolved. In these cases a different quality impact exists against a pre-existing standard of care associated with coded treatment costs. or acute myocardial infarct to chronic inflammation such as inflammatory bowel disease or orthopedics and wound healing.to latewww. Reimbursement decisions for a common product with multiple utilities are more likely to be driven by COGS than qualityof-life assessment. phase clinical studies. Manufacturing considerations and preclinical development guidelines have become routinized with formal Code of Federal Regulation and informal Regulatory agency policy available as information documents.Regulation. and culminating in extensive capitalization with the Mesoblast/Teva agreement.2] . ƒƒ Identit y. As a consequence. significant capital has come into this space exampled by the Athersys/Pfizer relationship. Driven initially by Osiris Therapeutics and an effective partnership with Lonza (previously Cambrex). using T flasks and labor-intensive procedures. Second. based upon less than expected clinical outcomes in the first generation of mid.

which is a wise decision. Gaps also exist in efficient product fill and storage alternatives for scaled manufacturing. Millipore) are in development. Automated product fill bioprocessing tools developed for biologics are not suited for particles such as cells that settle significantly on a fill line. and it is likely that platforms in this class can successfully meet near-term bioprocessing needs. Current controlled rate freezers were developed to process blood cell bags or vials at small scale. Terumo BCT) and counter flow centrifugation (kSep. due to extensive development costs. Large-scale evaluation of volume reduction using 50 billion cells costs US$750. these technologies are not significantly reducing COGS and have other associated disadvantages. are logical neutral testing centers for public domain process improvements. Cell collection technologies are only in their infancy without adoption and implementation in clinical testing. (2012) 7(6 Suppl. Adaptations of tangential flow filtration (Pall. The development costs associated with performing large-scale cell expansion and downstream processing development may be prohibitive against current available market capital. primarily the absence of downstream cell collection and formulation capacity. the last few years have shown strengthened cooperative initiatives and evolution of industry segments within regenerative medicine societies. insufficient stability experience has been gained for full validation.) Industry initiatives are now proceeding to form consortia for solving downstream processing requirements common to all therapeutic manufacturers. Strong lobbying and education influence is being driven by societies such as ARM and ISCT. Organizations like Bioprocessing International have aligned with ISCT and Alliance for Regenerative Medicine (ARM) for crosscommunication of clinical development progress and manufacturing perspectives to provide the bioprocessing industry with an assessment of growth opportunity and encouragement to develop products in this space. While the industry is moving towards product fill in cryovials and away from bags. Invetech) are very promising approaches with cell processing history in the blood cell industry. however. Regen. The Society for Biological Engineering has integrated manufacturing aspects of cell therapeutics into their focus. These technology gaps exist as a consequence of unproven market potential.000 cost (Figure 1). ­ Current top-end capacity in practice now yields approximately 1–5  billion cells. Progressive academic centers with strengths in bioengineering and bioprocessing. There are recent examples for cooperative crosstalk and encouraging signs for change. Much effort is going into evaluation of hollow fiber bioreactors. This is a daunting target to reach for. However. Scaled cell elutriation (Elutra. The bioprocessing industry has developed tools for downstream processing and large-scale volume reduction. but with focus on collecting biologics rather than cell products. as well as growth of cells on microcarriers suitable for use in stirred tank or packed bed bioreactors. How can community efforts solve manufacturing roadblocks? Academic and industry groups are now evaluating new thinking in manufacturing platforms for MSC and related products. In addition. With current industry standards for MSC production averaging US$15 per million cells. Med. such as UC Davis and the University of Loughborough. clearly scalable given their use in the vaccine and gene therapy industry. the most notable being the Industry Community of ISCT and the future science group . With many undetermined variables this is prohibitive for the bioprocessor and prohibitive for the therapeutic company. 80 Recruitment of the bioprocessing sector into this space can be influenced by the community effort of therapeutic manufacturers and their societies. and development and validation of large-scale freezing platforms and inventory storage devices are key. a large-scale evaluation of volume reduction using 50 billion cells poses a $750. Next-generation manufacturing platform targets would increase production campaigns approximately tenfold.Deans Figure 1. and are achieved by increasing the 2D footprint for production using larger cell factories or HYPERstacks® (Corning Life Sciences). resulting in inconsistent vialing. with concomitant requirements for robotic and mechanical tools for manipulation.000.

Deans R. Bake-off clinical studies are not currently required by the FDA and others. No writing assistance was utilized in the production of this manuscript. www. The International Society for Cellular Therapy position statement.alliancerm. and ISCT has placed global outreach as a high priority in its strategic initiatives. Le Blanc K. This includes employment.celltherapysociety. Commercialization of trials for peripheral arterial disease. Most importantly. and a second generation of initiatives on potency and cell characterization are coming forward. The regulatory environment in Europe is more supportive of investigatorbased initiatives for patient designated manufacturing with an evolving position on hospital exemptions as an allowance for autologous product manufacturing within the patient treatment clinical center. consultancies. Open code development principles Perhaps the most important principle facing the regenerative industry is the promotion of open code development principles. this evolution is also riding on the wave of MSC therapies. the development of technologies to utilize or create pluripotent stem cell biology is crafting yet another paradigm.com 81 .org/ 105 International Society for Cellular Therapy.Regulation. 4 Dahlke M. Dominici M et al . that of personalized medicine. It is not difficult to forecast that postnatal tissues will be collected at birth. Patel A. guidance. with genome sequencing determining predisposition for disease. with devices such as the Quantum® (Terumo BCT) and the Xpansion™ (ATMI) serving this purpose. Cytotherapy 9.gov/downloads/ BiologicsBloodVaccines/NewsEvents/ WorkshopsMeetingsConferences/ UCM200358. 614–619 (2009). the hematopoietic Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. stock ownership or options. 5102515 (2009). this is not the case. As mentioned above. Hopefully. What is the future? Ironically.ppt www. Stroke 40(2). Hoogduijn M. spanning stroke [3] . 301–302 (2007). Preparation for this is actually building within the bioprocessing industry. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Transplantation 88(5). www. transplant community was able to work with open disclosure around performance of tools and reagents for hematopoietic stem cell transplantation prior to product approval. 3 „„Websites 101 FDA update on cord blood regulation: new www. Sherman W. Horwitz E. with evolution of disposable bioreactors suitable for producing limited clinical product designated for an individual. while the universal donor concept around MSC has done so much to foster business models and solicit capital investment in the regenerative medicine space.com/ 107 Society for Biological Engineers. 315–317 (2005). Minimal criteria for defining multipotent mesenchymal stromal cells. solid organ transplant [4] and peripheral vascular disease [5] .aspx 104 Foundation for the Accreditation of 2 5 Cellular Therapy. 1157–1161 (2011).ac.lrmn.org/ 103 Engineering and Physical Sciences Research Council. The first collaborative publication by these members is in press in Cytotherapy on the subject of potency assays. Eggenhofer E et al .epsrc. Mazouz C. we can look beyond short-term competitive instincts and understand the value of building an industry segment emphasizing the patient and able to compete in new world pharmacoeconomic order. or royalties. www. manufacturing & building industry consensus momentum established by ARM. www.aiche. grants or patents received or pending. honoraria.fda. Towards MSC in solid organ transplant: 2008 position paper of the MISOT study group. We are unfortunately a good distance away from alternate MSC products carrying a label like a can of soup describing effective potency. Cytotherapy 8. The Alliance for Advanced Therapies has been launched as a sister organization for ARM. Cytotherapy 13(10). More importantly is the willingness of industry to contribute clinical data for product classes to clinical data registries.org/sbe future science group www. This has several dimensions – several organizations have worked extensively to structure workshops and publish standards for preclinical models and clinical end points and trial design. LeBlanc K. 102 Alliance for Regenerative Medicine. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. these societies are striving to have an international voice. expert testimony. Stem Cell Therapies as an Emerging Paradigm in Stroke Participants. www. With MSC as a case study. These organizations have invited and exposed regulatory agencies to these workshops for the purpose of crafting testing standards to support success in these sectors for all. Mueller I et al. ­ References 1 Dominici M. Interestingly.uk/Pages/default.org/ 106 London Regenerative Medicine Network.futuremedicine.factwebsite. and it is not clear if and when products within a class will be required to demonstrate superiority as a requirement for approval.

com/ bl r volume 14 number 1 • 2012 • issn 2152-4971 Cellular Reprogramming formerly Cloning & Stem Cells Rejuvenation Research Editor-in-Chief Aubrey D. OBE.com/aid WOUND-cover-FINAL-090811.indd 1 9/8/11 11:40 AM w w w .liebertpub.com/cell CELL-14n1. FRS. FRSE Editor-In-Chief www.e n i c i d e M e v i t a r e n e g e R n i s n Innovatio Ensure your access to the most groundbreaking Advances in Wound Care Chandan K.indd 1 1/13/11 11:13 AM www.liebertpub.com/recommendlibrary .liebertpub.J.l i ebert pub. de Grey Associate Editors Anthony Atala Augustinus Bader Vilhelm Bohr Judith Campisi Mario Capecchi Barbara Gilchrest William Haseltine Donald Ingram Thomas Johnson Edward Lakatta Mark Lane Anthony Linnane Graham Pawelec Daniel Perry Nadia Rosenthal Jerry Shay Gregory Stock Rudolph Tanzi Michael West Christos Zouboulis Stem Cells and Development Professor Sir Ian Wilmut.liebertpub.com/scd Subscribe or Recommend to Your Institution www. Sen Editor-in-Chief: AIDS Research and Human Retroviruses Biotechnology Law Report editor-in-chief: G e r r y J .indd 1 3/15/12 12:01 PM 44732_REJ_cover. el m a n executive editor: CHris HOlman Celebrating 30Y e a r s www.N.

com/hgtb HUM-cover-23n8.indd 1 www.com .indd 1 www.liebertpub.liebertpub.com/hum Tissue Engineering www.com/hum Part A Tissue Engineering Part B: Reviews Tissue Engineering Part C: Methods The Official Journal of Tissue Engineering & Regenerative Medicine International Society The Official Journal of The Official Journal of www.h c r a e s e R y g o l o and Biotechn research and applications in the field! Human Gene Therapy Methods including DNA.com/teb li b t b /t b 3/7/12 4:05 PM Tissue Engineering & Regenerative Medicine International Society 49151_TEC_cover.liebertpub.indd 1 6/28/12 11:41 AM www. and Cell Therapies Human Gene Therapy Clinical Development www.com/tec li b t b /t 3/12/12 1:14 PM 49291_TEA_v18n13-14_cover_2P.liebertpub.liebertpub.indd 1 6/21/12 2:38 PM www.liebertpub.com/tea Tissue Engineering & Regenerative Medicine International Society 49181_TEB_cover.liebertpub. RNA.

). these ‘policy agents’ serve as mediators of crossjurisdictional policy transfer and innovation by promoting transnational governance [4] while simultaneously urging jurisdictions to engage in normative action. REGULATION & ETHICS Commentary Alliances.79 © 2012 Future Medicine Ltd Regen. a global. which are mobilized across the globe in space and time [2] by the work of scientific alliances. McGill University area and Génome Québec Innovation Centre. This article provides a succinct review of the International Stem Cell Forum (ISCF). transformed and distributed across jurisdictions. Centre of Genomics and Policy.POLICY. (2012) 7(6 Suppl. By asserting legitimacy pressures. contributed to the convergence of normative and scientific standards. the Organization for Economic Co-operation and Development [105] . international and regional actors in a multidisciplinary and multidimensional manner [3. as evidenced by the proliferation of transnational stem cell initiatives. the first transjurisdictional organization of funders of stem cell research [102] . historical and political contexts greatly shape both the debates and policy outcomes. so are policy goals. the sustainability of the field is – to a great extent – dependent on the ability of such actors to enable cross-jurisdictional collaboration by fostering the sharing of stem cell-related resources and data [1]. 740 Dr Penfield. which targeted the complex problem of unproven stem cell interventions marketed around the world (‘stem cell tourism’). models and mechanisms for implementation. The power of these institutions in fostering scientific progress by promoting best practices and policy *Author for correspondence: Rosario Isasi. best practices developed by these actors are also promoting prospective policy evaluation. Notable examples are: the International Society for Stem Cell Research (ISSCR) [103] .4] . derivation. Professional organizations. somewhat paradoxically. alliances. rosario. Faculty of Medicine. a global governance and educational tool was promoted with ISSCR’s initiative ‘A Closer Look at Stem Cell Treatments’ [105] . storage and distribution) still remain within and between jurisdictions. networks and institutions. the EU [104] and finally. Efforts directed at addressing the challenges posed by globalization are flourishing. which in 2009 launched the ‘Stem Cell ISSN 1746-0751 Alliances. the globalization of the stem cell field has. such as the ISSCR [103] . Suite 5206. networks and other institutions. While heterogeneity of national policies governing stem cell research at all its stages (collection. collaborations and consortia: the International Stem Cell Forum and its role in shaping global governance and policy Rosario Isasi* It can be asserted that the stem cell field be classified as a global enterprise [1] .2217/RME. Kofi Annan’s statement that “arguing against globalization is like arguing against the law of gravity” [101] could not be more true when applied to the context of stem cells. Med. Furthermore. provide an institutional foundation for the development and dissemination of best practices. the ISCF [102] together with the International Consortium of Stem Cell Networks [5] . prospective and ethical framework has also been promoted by the Canadian Stem Cell Foundation. as they in turn build on the knowledge and experience of other institutions and jurisdictions in developing and implementing policy frameworks [7] . innovation should not be underestimated. 84–88 . as well as governance and ethical principles (Figure 1) [1] . Additionally. transparent and uniform practices worldwide [107] .isasi@mcgill. use. Department of Human Genetics.12.ca 84 10. It examines three ISCF initiatives as examples of how international consortia can help shape global governance and scientific practice. particularly with respect to the ongoing need for governance and policy interoperability. as well as the Inter-State Alliance on Stem Cell Research [6] . International Stem Cell Forum: Ethics Working Party area. ISSCR has been fostering global governance and international cooperation in stem cell research and clinical translation since its inception [106] through the adoption of guidelines seeking to promote responsible. Moreover. Given that socio–cultural. collaborations & consortia & the shaping of global governance and policy Policy transfer is conducted by a range of national. As a vast range of pluripotent stem cell lines are continuously immortalized.

Lux. SCNT: Somatic cell nuclear transfer. SCNT) Intermediate approach (restrictions in place fo hESC research and derivation) Restrictive approach (prohibitions on embryo research or on derivation and use of hESC embryos. IVF: In vitro fertilization. or research limited to imported hESC lines) Sweden Norway Denmark Estonia Latvia Lithuania Finland future science group No specific legislation in place regarding embryo or hESC research Federated country where hESC and derivation are both a matter of federal and state law.) www. Austria Slovakia France Switz.futuremedicine. Germany Poland Belgium Cz. (2012) 7(6 Suppl.com Brazil South Africa Argentina Taiwan Vietnam Thailand Philippines Panama Colombia Singapore Peru Australia Figure 1. Rep. Policy approaches range from permissive to restrictive UK Neth. hESC: Human embryonic stem cell. Redrawn from [111].Permissive approach with respect to hESC research derivations (IVF. New Zealand 85 . Hungary Slovenia Romania Georgia Bulgaria Italy Portugal Spain Turkey Ireland Greece Tunisia Malta Cyprus Iceland Canada USA China Israel India South Korea Japan International Stem Cell Forum & its role in shaping global governance & policy Regen. Current laws and policy approach on stem cell research globally. Med.

given that their authority for enforcement and accountability. Founded on the values guiding the protection of human rights. ƒƒ Considering issues relating to the management of intellectual property in stem cell research and development. The International Stem Cell Forum members have agreed a set of key principles that determine their approach to stem cell research. The EWP recognizes the complexities of the stem cell field. International cooperation and transnational education are also the remit of the International Consortium of Stem Cell Networks [5] . is virtually absent. professional organizations employ the power of persuasion as their main tool with regards to policy transfer. The ISCF was established in 2003 under the auspices of the UK Medical Research Council. ƒƒ Intellectual Freedom to exchange ideas in the spirit of international collaboration. (2012) 7(6 Suppl. boundaries and disciplines. ƒƒ Analyzing ethical issues in stem cell research. as well as the ability to prevent and treat disease. As such. ƒƒ Integrity in the promotion and advancement of stem cell research and therapy for the betterment of the welfare of all human beings. the realization that this could only be achieved through the promotion of international collaboration and funding support led to the launch of the ISCF [102] . despite the globalization phenomena.Isasi Charter’ [8] . horizon scanning and analyzing ethical issues and policy frameworks regarding stem cell research and stem cell-based therapies. Their innovative approach seeks to expand “the concept of national research networks to the international level” with a series of knowledge transfer activities fostering the exchange of best practices [5] . These principles are: ƒƒ Responsibility to maintain the highest level of scientific quality. The ISCF-EWP aims to identify the different national ethical–legal and policy landscapes [10] . In fact. ƒƒ Identifying key research gaps and addressing them by capitalizing on national strengths. which is characterized by a vast range of pluripotent stem cell research and potential therapies. The ISCF-EWP work program is designed to be prospective and responsive to the dynamic nature of policy and regulatory environments. The ISCF Ethics Working Party (EWP) is an independent body mandated to review fundamental ethical policies pertaining to stem cell research. in order to facilitate international dialogue on fundamental ethical issues. via monitoring. ƒƒ Fostering training for researchers worldwide in the handling. ƒƒ Transparency through the disclosure of results and of possible conflicts of interest. as well as ethical and regulatory issues surrounding stem cell banking [13] . and was comprised of 21 funding organizations of stem cell research around the world. Areas identified by ISCF members where joint work would be particularly beneficial: ƒƒ Encouraging collaborative research across nations. As with other actors. the use of monetary payments for the procurement of oocytes for stem cell research [12] . Funding organizations have an essential role to play in fostering international cooperation and promoting scientific integrity while accelerating scientific progress. safety and ethical probity. which are performed in a context of political and cultural diversity [108] . and to foster shared ethical principles so as to guide the conduct of stem cell research and policy making. the EWP’s seminal policy statements on the managing of genetic data [14] and the disclosure research results and incidental findings in the context of stem cell research and banking [15] continues to inform scientific practice. They are: ƒƒ Opposition to human reproductive cloning ƒƒ Use of adult somatic human stem cells. To achieve its objectives the ISCF supports three major international initiatives. As the ISCF-EWP fulfills this mission. it has focused on analyzing substantive requirements and procedural safeguards in the regulation of stem cell research [11] . Med. as well as the rapid pace of scientific developments.) The ISCF Once it was established that the true potential of stem cell research was 86 future science group . improving scientific knowledge. ƒƒ Promoting sharing of resources and data. growing and expansion of human stem cell lines. with the overall objective to promote global good practice. Moreover. ƒƒ Protection of citizens from harm and the safeguarding of the public trust and values. including cell lines. as well as embryonic human stem cells ƒƒ The generation of embryonic human stem cell lines should be minimized ƒƒ International harmonization of ethical and intellectual property rights Regen. ƒƒ Facilitating transnational collaborations via funding schemes. The International Stem Cell Forum key principles. including their capacity to impose sanctions. the Charter articulates five principles advocating responsible stem cell science. scientific protocols and guidance documents. Box 1. the EWP continues to prospectively identify issues that are in need of ethical deliberation and further policy guidance. governance remains almost entirely the role of national authorities [9] .

futuremedicine. role models and agents. Indeed. characterization. 11 International Stem Cell Forum Ethics 7 Working Party. 5(1). Genetics Policy Institute. Policy transfer and learning in the field of transport: a review of concepts and evidence. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. Letter to the Editor: oocyte donation for stem cell research.695933 (2012) (Epub ahead of print). Human Reprod. The ISCI was created in 2004 with the view of establishing criteria and techniques to support the development and use of human embryonic stem cell lines for medical applications [19] . USA. 108–115 (2009). Willemse L. The International Consortium of Stem Cell Networks (ICSCN). Knoppers BM. Pol. 12 For the International Stem Cell Forum 4 8 9 5 Ethics Working Party: Knoppers BM. working jointly towards indentifying and harmonizing best practices for banking. Lyall A.com 87 . scope. maintenance and shipment. Isasi R. which published the results of the work carried out by ISCI projects. USA. Beyond the permissibility of embryonic and stem cell research: substantive requirements and procedural safeguards. 32. Riin Kruusenberg A. A set of best practices for clinical-grade pluripotent stem cell lines is currently being developed by ISCBI. which was charged to compare the performance of different media for the culture of hESCs and to study the genetic changes that can occur in hESCs on prolonged passages in culture [21] . ISCI groundwork is divided into three initiatives: the ISCI-1 main objective was to systematically define key features of human embryonic stem cells (hESCs) and to establish whether or not hESCs share common features. Isasi RM. Policy studies doi:10. 21(10). 19(2). Rev. The latter is reflected in the challenges ensuing from the controversial phenomenon of stem cell tourism [24] . alliances. In 2008. 10 Isasi RM. Despite the strengthening of international consortia seeking to accelerate scientific progress by promoting collaboration via the sharing of resources and the establishment of best practices. stock ownership or options. Forsberg EJ. 5–6 (2010). Health Law 13(1). Richardson G et al.International Stem Cell Forum & its role in shaping global governance & policy The International Stem Cell Banking Initiative (ISCBI) has been established with the vision of creating a global. ISCI-1 identified “a set of standard markers that could be used to characterize and monitor the behavior of hESCs in future experiments” [109] and established the ISCI Registry [110] . Transfer and translation of policy. characterization and testing of pluripotent stem cell lines [16] . The ISCI-1 enlisted the work of 17 laboratories (spanning 11 different countries) to analyze 59 independent hESCs and established a globally agreed upon set of criteria for characterizing stem cell lines [20] . Genetics Policy Institute. safety testing and international distribution. Science 316. No writing assistance was utilized in the production of this manuscript. or royalties. Important harmonization and standardization work has been carried out by ISCBI. have a major role to play as agents both for policy transfer and global governance. World Stem Cell Report (2010). Public Adm. governance. Revel M. Funding consortia. Knoppers BM. Med. Stone D. Stem Cell Rev. Conclusion Foresight and global approach to scientific innovation are two characteristics of major national and transnational stem cell initiatives. Regen.1080/01442872. Mind the gap: policy approaches to embryonic stem cell and cloning research in 50 countries. Transport Policy 18(3). 6 2 3 Lomax G. ­ References 1 Isasi R. such as the ISCF. quality control. Stem Cell Charter. 154–166 (2012). It is envisaged that ISCBI will have an important role to play in shaping research and its clinical translation by creating the foundations for stem cell banking [17] . J. The new guidelines will establish an international set of standards for stem cell lines destined to be used in clinical translation as well as clinical trials. expert testimony. an effective global governance framework is yet to be consolidated. Stead D. honoraria. testing. 151–180 (2002). ISCBI adopted its first best practices: the ‘Consensus Guidance for Banking and Supply of Human Embryonic Stem Cell Lines for Research Purposes’ [18] . Res. ISCBI’s vision and mission is “to create a solid scientific and ethical framework for international stem cell banking and research” [17] . ISCI-3 is entrusted to establish a consensus on quantifiable protocols that can be used to assess the capacity of individual pluripotent stem cell lines (ES or iPS) to differentiate along specific lineages [22] . grants or patents received or pending. 9–25 (2006). future science group www. Policy transfer in immature policy environments: motives. This was followed by ISCI-2. Randma-Liiv T. World Stem Cell Report (2010). The review of policy research (summer 2002). 366–367 (2006). Policy harmonization through collaboration: the interstate alliance on stem cell research. 2474–2481 (2006). networks and institutions. and will cover procurement. 5(2). Marsden G. consultancies. Finally. An integrated approach to policy transfer and diffusion. The International Stem Cell Initiative (ISCI) recognizes the importance of scientific consortia in high-quality scientific practice by promoting standardization. Policy interoperability in stem cell research: demystifying harmonization. This includes employment. 492–500 (2011). Science 312(5772). banking procedures. Newmark AJ. This guidance document seeks to be comprehensive in managing a wide range of aspects involved in a bio­ resource: from procurement to ethical provenance. interoperable network of stem cell banks. 368–369 (2007). Gincel D et al. 107–110 (2010). 100–103 (2010). the ‘globalization’ of the stem cell field has shifted the sphere of debate and action from national to the international [23] . Knoppers BM. Ethics issues in stem cell research. Eur. Dev.


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Working Party. The disclosure and management of research findings in stem cell research and banking Regen. Med. 7(3), 439–448 (2012).
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Regen. Med. (2012) 7(6 Suppl.)

future science group



Cell standardization: purity and potency
Belinda J Wagner*
The regulatory requirement to demonstrate purity and potency presents a much bigger challenge to regenerative medicine compared with small-molecule drugs and protein biologics because of the desire to introduce living cells into the human body. Any cell population is inherently heterogeneous and bioresponsive – characteristics that make standardization by traditional methods extremely difficult. Standardization is on a ‘critical path’ to demonstrating purity and potency as I will discuss. Although difficult, I believe standardization is not impossible. In fact, I believe untapped resources of benefit to the regenerative medicine and cell therapy industries exist, particularly in the area of oncology molecular diagnostics. Leveraging the vast amounts of cellular biomarker data that are linked with clinical outcomes and the established reimbursement strategies generated by oncology product development efforts might accelerate the translation of regenerative medicine products from the bench to the clinics both scientifically and financially. The technical difficulty of establishing purity and potency for a therapeutic using standardized methods increases with the complexity of the therapeutic’s structure and the potential for variability in the processes by which it is manufactured. Both the complexity of therapeutic structure and the potential variability in manufacturing processes have increased dramatically. One can divide this complexity into three major categories (Figure      1). The least complex are small-molecule therapeutics produced by chemical reactions. More complex are biopharmaceuticals (e.g., recombinant human proteins, fusion proteins and monoclonal antibodies), where living organisms (e.g., plant and animal cells, bacteria, viruses or fungi) produce the molecule, which is then purified. The highest complexity is cell-based therapeutics, where viable cells are introduced into a patient, whether as cells alone or as components of a combination product. Another perspective is to look at product characteristics that are relevant for establishing purity and potency. The final products of both small-molecular therapeutics and biopharmaceuticals are fairly static entities. Environmental conditions can affect them, but the effects are predominantly chemical or conformational. Living cells are another matter entirely – very subtle or dilute environmental cues can trigger cascade effects that change both the intra­ c ellular and extracellular environments extremely rapidly. Even clonal cells expanded in culture are not identical; they are heterogeneous populations, harboring differences that change over time. Depending on when a sample is taken, aliquots of living cell populations can have different percentages of cells at each phase of the growth cycle, signaling pathways can have different sensitivities and so on. Getting reproducible results from separate in vitro experiments often requires extremely tight control of both timing of process steps and reagents. Human bodies, particularly human bodies that harbor disease conditions that can take decades to establish, are not so well-controlled. Both the population and bioresponsiveness characteristics of cells are a double-edged sword. On the one hand, by being bioresponsive, cells can respond to the environment into which they are introduced in a more tailored manner. For example, diabetic patients requiring insulin must calculate the correct dose to administer multiple times a day. Insulin pumps have simplified the delivery of a correct dose, but problems with blood sugar management still occur. A cell therapy approach would treat insulin-dependent diabetes with bioresponsive pancreatic b -cells, placing them where they would have access to the same sensing mechanisms as native b -cells would in a nondiabetic patient, to deliver the right amount of insulin to the bloodstream continuously. On the other hand, a small subpopulation of cells within a delivered dose could react to the patient tissue environment in an unanticipated way. For example, certain cytokines can tip the balance between stimulating or suppressing inflammation depending on whether they are present in low or high concentration, or if they are present in certain combinations with other cytokines. A small
ISSN 1746-0751

*Author for correspondence: Belinda J Wagner, Biographic Design Consulting, Winston-Salem, NC, USA; phdnofuddy@yahoo.com

10.2217/RME.12.69 © 2012 Future Medicine Ltd

Regen. Med. (2012) 7(6 Suppl.), 89–92



Cell-based therapeutics


Small-molecule therapy

Levels of complexity

Figure 1. Complexity of therapeutic structure.

percentage of cells could be primed to trigger an inflammatory cascade, which could then influence the entire dose of cells to respond by stimulating inflammation. Such unanticipated population shifts could trigger an adverse event in a patient. How do we develop cell therapies that reap the benefits of bioresponsiveness and avoid the pitfalls? By adhering to basic principles of standardization, identity, purity and potency in the context of heterogeneous populations of living cells.

Standardization Standards became highly important during the Industrial Revolution with the need to make interchangeable parts. In the life sciences, standards help data become more interchangeable by providing a common comparator for results.
A simple illustration of a situation where standardization is lacking in cell therapy product discovery is provided by a widely used procedure to isolate mesenchymal stromal cells

(MSC) – applying a cell suspension (e.g., mononuclear cells from bone marrow or the stromal vascular fraction from adipose tissue) to tissue culture plates and expanding the population of cells that adheres to the tissue culture plate surface. Some of the parameters that could vary among preparations are the procedures and reagents used to generate the cell suspension, the surface composition of the tissue culture plates, the media components used to nourish the cells during the adherence phase, the relative proportion of adherent to nonadherent cells and so on. Variation in any one of these parameters can change the overall composition of the resulting ‘MSC’ population, making it almost impossible to compare results obtained with MSC prepared by separate groups, even if those groups isolated cells from different aliquots of the same tissue.

of MSC) stems from the relatively limited parameters used to identify cells as MSC. The British Standards Institution Publicly Available Specification 93:2011 defines an identity test as being “capable of distinguishing the cellular active substance from any other cells that might reasonably be present in the cellular starting material or final cell therapy product” (p. 5). Rare is the published study that characterizes the proportion or identity of nontarget cells present in the cellular starting material; more rare are published studies that track the dilution of such potentially undesirable cell types in the final cell therapy product; and even more rare are studies that evaluate whether the presence of cell types that are removed from the cellular starting material are deleterious to the observed in vivo effects of administering the final cell therapy product. The first step toward standardization in cell therapy is establishing a body of published work where each study contains the basics of defining identity tests for targeted and other cell types that meet the threshold defined in British Standards Institution Publicly Available Specification 93:2011 [1] ; measurfuture science group

Identity & its relationship to purity & potency Part of the difficulty of comparing results from supposedly related studies (like those evaluating the clinical utility
Regen. Med. (2012) 7(6 Suppl.)

standards can be developed that allow comparison of independently produced cell therapy products at different stages of production. and post-treatment. particularly in linking identity characteristics of both target cells and discarded cell types to clinically relevant responses. Microfluidics technologies can sample living cells within closed systems. ­ Mass spectrometry is being used to establish proteomic profiles and to detect specific peptides that signal beneficial or deleterious expression in blood and tissue samples. and establishing whether cells that are removed during production elicit adverse effects in vivo – either alone or in combination with the final cell therapy product (potency). More studies at the earliest phases of product discovery should document not only the presence of the active cellular population. Like cell therapy products. but could serve to measure equivalence between production processes at different sites or at different phases of scale-up. Such reference standards allow mechanistic parameters that might account for different clini- cal outcomes to be measured objectively without divulging intellectual property. Reference material scaffolds are being developed that can serve as a calibration point for comparing scaffold measurements between different laboratories. Once biomarkers that are correlated with clinical outcomes are identified through establishing a body of published work connecting the basics of identity and its relationship to purity and potency. more work needs to be accomplished in the foundational concept of identity. intermediate production steps. of relevance to cell therapies that use scaffolds. www. These data can be published in a manner that informs the overall field of cell therapy while maintaining the confidentiality of intellectual property critical for investment (process. Multiplexing capabilities are being developed to leverage the advantages of imaging using sample formats that are limited in quantity. One such example. Developing analogous reference materials for cell therapy biomarkers would not only allow comparison between different cell products. but are there paths forward that could leverage such understanding that has matured in other fields? I believe so.Cell standardization: purity & potency ing the proportion of target and other cell types in cellular starting material. A second-generation reference scaffold is under developement that will focus on measuring cell response (adhesion and proliferation) to 3D scaffolds. Also beneficial to cell therapy is the fact that many of these data have been assayed in huge numbers of clinical samples (prediagnosis. is the reference materials scaffolds being developed by the National Institute of Standards and Technology (NIST) (Figure  2). but its proportion in the starting material relative to other cell types and whether the persistence of other cell types or the presence of Figure 2. during treatment. tumors are a heterogeneous population of cells. Reference material scaffolds. ­ In summary. Most beneficial to the financial support of cell therapy product development is the linkage of oncology molecfuture science group ular diagnostics to both the traditional pharma investment paradigms and to validated assay systems that have wellestablished reimbursement pathways. Genetic stability is being monitored at the population level by focusing on shifts in mitochondrial DNA sequences. Therefore. RT-PCR-based assays can provide similar surveillance for gene expression. composition of matter and so on). Many of the techniques being developed to less invasively sample patients for diagnosis. treatment monitoring. Most promising paths forward Overall. One of the most promising landscapes that cell therapy could leverage is oncology molecular diagnostics. often for extended timeframes) and the growth of such data is still in log phase.futuremedicine. in order for the cell therapy industry to realize the economic benefits of standardization. The first-generation reference scaffolds have been deployed and focus on scaffold structure and porosity. it should be possible to assess the background of candidate biomarkers in a variety of target patient populations retrospectively or gather prospective data via IRB-approved protocols in institutions conducting clinical trials. and post-treatment surveillance are geared toward population sampling. and final cell therapy product (purity). the field of cell therapy still needs to develop further maturity in its understanding of identity before standards for purity and potency can be developed. NIST: National Institute of Standards and Technology.com 91 .

Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.) future science group . ­ Website 1 British Standards Institution. PAS 93:2011 Characterization of human cells for clinical applications. (2012) 7(6 Suppl. No writing assistance was utilized in the production of this manuscript. London. www. 2011. or royalties. This includes employment. 92 Regen. honoraria. UK.com/upload/Standards%20 &%20Publications/PSS/PAS93-2011. Leveraging the maturity of standardization that exists in oncology molecular diagnostics might be a promising direction in which the ability to develop standards for cell therapy might be accelerated.Wagner alternate biological states of the active cellular population elicit deleterious effects in vivo. consultancies. Med. expert testimony. stock ownership or options. Department for Business Innovation and Skills. grants or patents received or pending.bsigroup.pdf (Accessed 10 July 2012).


With 30 years of laboratory and clinical efforts fueled by countless billions in public and private funding. 94–97 . however. justify a regulatory framework that stalls the clinical development of these technologies.g. we estimate that there are approximately 350 stem cell clinics worldwide seeing an average of five tourists per month. but rather. Cytograft Tissue Engineering. This does not. today. CA 94949. abdominal aortic aneurysm repair or transcatheter valve devices) are developed through an Asian. While recent analysis has suggested that regenerative medicine is maturing into a multibillion dollar industry. CA 94949. Moreover. examples of clinical and commercial success are still relatively rare [1–3].12. Novato.6] .000 resulting in an annual spend of over US$500 million on unregulated stem cell treatments. it is clear that the regulatory framework in the USA has played a prominent role in creating a stem cell ‘tourism’ industry. David Audley & Nicolas L’Heureux Cell-based therapies (CBTs) have been hailed for the last two decades as the next pillar of healthcare.2217/RME. scientific. Clearly the FDA’s risk-averse stance toward the clinical use of high-risk medical technologies has influenced the commercialization of medical innovation. While it may be unfair to correlate the slow progression of CBTs solely with an overly exuberant FDA. Novato..e. REGULATION & ETHICS Opinion Autologous cell therapies: challenges in US FDA regulation Todd N McAllister*. While the USA still plays a prominent role in the discovery phase. Cytograft Tissue Engineering. that at the height of the negative press surrounding stem cell tourism. That said. Vioxx. While it is difficult to accurately assess the size of this market. have brought the situation to the forefront of both the scientific and lay press [15. USA 94 10. Suite 220. 3 Hamilton Landing. Here. the FDA’s conservative stance is somewhat understandable in light of the unfairly harsh press and political fallout surrounding previous failures (e.104] . Through interviews we have estimated that each treatment costs approximately US$25.16] .000 medical tourists.. The most striking of recent events is the dismissal of the lawsuit against the FDA brought by regenerative sciences [14] . This court case. or even legal background. with its zero-risk stance. This departure serves as a sad reminder of the negative economic and clinical impact of an ultraconservative approach. stymies clinical innovation while fueling a potentially risky medical tourism industry. silicone breast implants) as well as societal and legal trends toward zero-risk [7–9] . yet the clinical and commercial potential of regenerative medicine has yet to live up to the hype. It is ironic..000.POLICY. 3 Hamilton Landing. Novato..83 © 2012 Future Medicine Ltd Regen.000 stem cell medical tourists each year out of a total of 3. then.or EU-centric pathway. It would seem that the availability of adult autologous stem cells should ISSN 1746-0751 *Author for correspondence: Todd N McAllister. USA Nicolas L’Heureux. like other recent medical innovations (i. Suite 220. No one will argue that it is challenging to produce guidance documents at a rate matching the evolution of CBTs. (2012) 7(6 Suppl.7% of the overall medical tourism patient flow and about 3% of the total revenues (assuming total worldwide revenues generated by medical tourism are US$15 billion) [101. and FDA warning letters sent to physicians harvesting stromal vascular fraction. Med.102] . in combination with a lawsuit from Cytori Inc..). Inc. Geron’s recent exit from the field of regenerative medicine after a US-centric strategy is attributed by most observers directly to the FDA’s aggressive stance and protracted pathway to initial human testing [4] . This represents approximately 0. one must contemplate why CBTs have not made a greater impact. Inc. 3 Hamilton Landing. a religious or ethical background [14.. Adding to the irony is the fact that some of the most vocal and influential participants in this debate come not from a medical. Suite 220. Cytograft Tissue Engineering.103. Inc. the FDA is an underfunded and understaffed agency in the unenviable position of trying to regulate the best-funded and most innovative biomedical industry in the world. moves by the Texas Medical Board. Most CBTs. we highlight the challenges the US FDA faces and present talking points for an improved regulatory framework for autologous CBTs. giving a total of 21. USA David Audley. The current regulatory environment. the FDA is exerting an even greater influence in attempting to redefine CBTs and cracking down on USbased clinics conducting point-of-care treatments under the practice of medicine [10–13] . CA 94949. few technologies are translated to initial clinical use through the US regulatory framework. and supports such conclusions made elsewhere [5.

On one end of the spectrum is the academic community.000 Americans are dying every year from congestive heart failure or complications of myocardial infarction awaiting the outcome of this debate [18] . as their (typically) allogeneic products may be threatened by autologous.Autologous cell therapies: challenges in US FDA regulation be based on rational safety and efficacy arguments. and encourages continued bench-top and animal research. this community tends to echo the FDA’s conservative stance. point-of-care therapies. While there are a variety of ways to streamline the overall review process without introducing undue risk. the NIHfunded academic community is well served by a regulatory policy that promotes a longer and basic researchintensive developmental path. Meanwhile. is that there are few tools by which regulators or patients can objectively measure risk–benefit. incentives and biases outlined above. it is remarkable that only a few thousand patients have been treated in the USA and EU since the first human use more than a decade ago. as it exists today. it is difficult to contemplate a major shift in the existing regulatory framework. as industry lobbies for tougher regulations for point-ofcare therapies in an effort to create a more significant barrier to entry for autologous therapies offered by these physicians. we must consider this situation from the perspective of the patient. Given the safety and efficacy that both autologous and allogeneic stem cells have demonstrated for myocardial regeneration. for example. it is unforgivable that CBTs have not been made more readily available. it is important to objectively recognize the biases. and creates an economic sinkhole for the federal government. however. autologous therapies represent a real threat to the penetration rates most commercial entities project. the extensive costs associated with FDA regulation and manufacturing oversight of massproduced allogeneic cells may negate these theoretical cost savings. trying to balance clinical innovation with their mandate from Congress to maintain public safety. the situation is primed for disappointment and potentially unnecessary health risks. it is difficult to make the same argument. While we sink billions into federally funded research.000. shortcomings and financial incentives held by the various stakeholders. With no clear efficacy benefit for most patient populations. few therapies reach the clinic to make a positive impact on public health. While critics understandably point to the poor risk–benefit ratio associated with less scientifically justifiable treatments. it is no wonder that desperate patients look to stem cell therapies for hope. However. Perhaps most importantly. then. As we analyze this situation and try to provide improved regulatory paradigms. the FDA’s concerns with tumorigenesis for stem cell treatments targeted at congestive heart failure. In theory. is not the risk of communicable diseases or tumorigenesis. Indeed it is puzzling to contemplate. this vision is sullied by images of rogue clinics that operate without regard for patient safety or benefit [106] . it is puzzling to see the same arguments applied to clinics performing orthopedic procedures.futuremedicine. point-of-care therapies. for example. The real problem with point-of-care autologous therapies.’ As opposed to developing a streamlined process for evaluating the 95 . With few objective tools to help guide them. with enormous financial incentives tied to stem-cell treatments that can cost in excess of US $20. Here the potential conflict of interest is more evident. For autologous. point-of-care. While justified in many cases. While physician-based societies such as the International Cellular Medicine Society tend to advocate clinical innovation and the delivery of therapies under the scope of the practice of medicine. however. With pressures from the NIH roadmap to focus on translational research. allogeneic products should be cheaper to manufacture and administer than autologous therapies. it will be interesting to see how this viewpoint evolves. who argue that point-of-care therapies help fuel medical innovation and can be adequately regulated by state medical boards.com therapies. the situation as it exists today is a disservice to patients. myocardial regeneration. is a significant driver in building ‘stem cell tourism. Unequivocally. Caught in the middle of competing stakeholders these three  is the FDA. For allogeneic therapies. Meanwhile. and puts significant manufacturing and quality assurance hurdles in place to minimize the risk of product failures that can affect thousands of patients. Fueled by wild promises of efficacy and fantastical images in the lay press. lower limb angiogenesis. there are several points that most experts would objectively agree upon: ƒƒ The restrictive FDA regulatory framework. and generally lower than alternative www. That is. we cannot ignore the potential financial self-interest served by this message. The fundamental problem. Through societies such as the International Society for Stem Cell Research. the FDA rightfully looks at these allogeneic products as mass-produced technologies. and the debate should be driven by individuals with the training and experience to appropriately evaluate the risk and benefit associated with manufacturing controls or treatment methodology. Indeed it is no surprise to see the International Society for Stem Cell Research closely linked to the war on stem cell clinics [17. future science group Industry plays an important role in this ethical and legal debate. Despite the various perspectives. however. approximately 200. for example – those risks are easily mediated by reasonable manufacturing and safety measures. Given the lack of alternatives for these patients.105] . Americans funnel hundreds of millions of dollars to offshore clinics. This makes for strange bedfellows. On the other end of the spectrum are physicians delivering point-of-care therapies with autologous cells.

This new regulatory framework would mimic elements of the FDA’s existing tiered structure I. outside of the legal and regulatory oversight and authority inherent within the US healthcare system. ƒƒ The tolerance for risk in target patient populations is directly linked to the severity of the disease and the likelihood of recovery with standard medical therapy. Sadly. ƒƒ While there is a precedent for regulating CBTs under the practice of medicine (i. Med. Animal studies with CBTs do disappointingly little to alleviate risk or convey efficacy in human models. such as Parkinson’s or Alzheimer’s. ƒƒ A mandatory data collection registry that captures patient outcome data and that would be shared with healthcare authorities to monitor different protocols for differential evidence of safety and efficacy. processing and delivery of cells and whose facilities and protocols have been properly evaluated. Moreover. while not zero.. there does not appear to be a safety issue associated with cell-viability. require appropriate quality control guidelines. values physician innovation and strives to balance patient risk with potential benefit. autologous stem cell therapies delivered under the umbrella of the practice of medicine have been portrayed as ‘snake oil’. there is little risk from a safety perspective in delivering a mixed population of autologous cell types across a wide range of dosages. cell aggregation-induced embolism or stroke. but rather. and perhaps most importantly. the real risks do not need to be managed by a regulatory framework designed for mass-produced. While there is admittedly no shortage of examples where this image is true.. even though there may be relatively little evidence for efficacy. ƒƒ It is neither cost–effective nor feasible to expect the same manufacturing quality controls for autologous therapies as those in place for mass-produced allogeneic therapies (just as one would not expect the same quality control burden in an operating room as in a device manufacturer’s clean room). the risks associated with short-term expansion (through ~p5) are relatively low and can be managed effectively through the use of closed loop systems or modest QA programs. ƒƒ The risks associated with the nonhomologous delivery of adult. and there is no real substitute for slow. cell population ratios and mechanistic data. in vitro fertilization [IVF]). thanks in large part to an alarmist focus on largely hypothetical risks. it is more likely that the most efficacious protocols will be derived from careful. Rather. tracking. (2012) 7(6 Suppl. it drives patients to clinics abroad. allogeneic therapies. represent a risk more akin to a surgery than a drug. autologous cells (i. has driven some of the most prolific periods of medical innovation. sterility. cancer. Whether under the umbrella Regen. ƒƒ Few prospective patients are adequately informed of the potential risks and benefits associated with CBTs. A patient would clearly understand the differences in efficacy for treatments for Alzheimer’s or Parkinson’s versus those for myocardial regeneration or critical limb ischemia. Over the last 5 years. in any way condone the unregulated free-forall that has evolved in many parts of the world.e. Similarly. ectopic tissue formation.e. however. Indeed this type of controlled clinical ‘experimentation’. II and III). we propose a new system that recognizes the strengths and weaknesses of classic drug clinical trials. It would. crosscontamination). Audley & L’Heureux safety and efficacy of autologous therapies. ƒƒ While efficacy may vary with cell purity or dosing. however. there is no state medical board framework in place today to train or monitor physicians in the safe isolation and delivery of CBT. however. These guidelines would require GMPs akin to those used in IVF but would not encumber a physician to perform years of benchtop research to identify the optimal cell concentration. many would agree that animal studies are not as predictive of human safety or efficacy as the FDA might suggest. ƒƒ While those in the field may assign various values to animal studies. ƒƒ With the exception of maintaining sterility. ƒƒ An independent accreditation process to give patients a tool to seek only physicians who have been adequately trained in the harvest. some of the US clinics that have developed ideal models for quality assurance systems and safety controls have been attacked and derided future science group 96 . ƒƒ Autologous therapies do not represent a public health risk in the same sense as a mass-produced drug. ƒƒ A tiered risk–benefit ratio for all therapies that would drive a consistent informed consent process. These points do not. controlled and monitored human studies rather than a Geron-like progression through hundreds of rodent studies. though largely absent in the USA now.McAllister. recognizing the (Class  risk–benefit differences between a marrow-derived injection for critical limb ischemia and intravenous injections for vague afflictions such as ‘aging’. it is clear that this broad brush should not be used to paint the entire field. is exceptionally low in practice and largely theoretical at this point. While admittedly a controversial concept.) of the FDA or State Medical Boards. disease transmission). preclude largely investigational therapies for debilitating diseases. It should not. establish reporting requirements for data collection. measured progression through initial human studies. we would establish a regulatory framework for autologous therapies that establishes: ƒƒ Basic quality assurance guidelines to target the most prominent risks associated with manipulating cells (training.

www.futuremedicine. Lysaght MJ. Med.com/video/ watch/?id=7394380n (Accessed 24 August 2012). Clinic taps patients’ own stem 7 cells to ease their pain.gov/ICECI/EnforcementActions/ WarningLetters/2012/ucm301620. 1707–1709 (2004). Lloyd-Jones DM et al. Stamp A. Coleman EA. 485 (2010). Deweerd E. www. the physicians and academia. have. 106 Pelley S. 351(17). Embryonic stem cell pioneer Geron exits field. 105 ISSCR emphasizes rigorous oversight for 6 vacation. Our objective should be to allow US-based stem cell clinics to deliver therapies with reasonable safeguards (that are not the same as drug manufacturers. An analysis of telephone interview data collected in 1992 from 820 women who reported problems with their breast implants to the food and drug administration. Silicone breast implants: lessons from the USA.org/ISSCR_emphasizes_ rigorous_oversight_for_application_of_ stem_cell_based_treatments/4573. 104 Malarkey MA. Langer R. Arguing against point-of-care therapeutics while holding up the sensationalistic banner of rogue clinics is a bit like trying to curb the transplantation field over concerns of organ trafficking.fda. Topol EJ. These illogical and counterproductive attacks simply drive patients abroad where standards are nonexistent. www. Engl. 17 Lerner M.htm (Accessed 23 August 2012). Lancet 379(9811). Burris R.htm (Accessed 23 August 2012). Scheithauer BW „„ Websites 101 Medical Tourism Statistics & Facts. Wall Street Journal 3 October (2011). Progress in the tissue engineering and stem cell industry “are we there yet?”. 93 (2012). Coon SK. FDA Impact on U. Korean deaths spark inquiry. Irrespective of which agency acts as the watchdog. Imagine today. FDA’s claims over stem cells IntelliCell Biosciences. 6(2). 60 minutes: stem cell fraud. Nat. Jaklenec A. 10 Amariglio N. Klasmeier C. 16th August (2012). the barriers a physician would face in developing successful transplantation protocols under the framework of the FDA. 11 Barclay E. Financial & competing interests disclosure The authors are employees of Cytograft Tissue Engineering. Andrews LB. www. Arlington. Genetic Engineering & Biotechnology News. Surg. 883–884 (2009).pdf 103 Malarkey MA. Failing the public health – rofecoxib. Indeed. e1000029 (2009). Hirshberg A. and do not strive for zero risk) to adequately informed patients in a transparent fashion. Fertil. Makower J. The FDA wants to regulate your cells. 348–355 (1984). Part B Rev. Lancet 373(9667). 42(3).cbsnews. Stem cell tourism hardly a Thomas E Young LLC. FDA warning letter to Nature 468(7323). application of stem cell based treatments. Meer A.S. Merck. Human in vitro 9 January (2012).fda.com/medicaltourism-statistics-facts 102 The rise of medical tourism 3 about medical tourism. it would seem clear that the FDA’s existing framework works poorly for these autologous applications. fertilization and the law.isscr. it is clear that an improved system with a rational policy toward risk–benefit would be a dramatic benefit to patients. Medical Technology Innovation: A Survey of Over 200 Medical Technology Companies. 909 (2010). 12 Cyranoski D.htm (Accessed 23 August 2012). Reconstr. Assuming that allogeneic and autologous treatments should be regulated the same is a disservice to patients everywhere. 14 Cyranoski D. and stem cell therapeutics. 13 Cyranoski D. physician innovation and significant clinical risks were certainly a major driver behind the success that the field enjoys today. Wall Street Journal 7 August (2012). 2 et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. 2043–2051 (2002).com/pdf/ ContenPodsPdf/Rise_of_Medical_ Tourism_Summary. 30(1). PLoS Med. Gottlieb S. Jaklenec A. Circulation 125(1). Tissue engineering: the end of the beginning. 8 9 Executive summary: heart disease and stroke statistics – 2012 update: a report from the American Heart Association. 188–197 (2012) 19 Quigley MM. Sherwin A. MJ Hazlehurst AL. Lemon SJ. While one can debate ad nauseam over whether the FDA or state medical boards can best manage an improved regulatory framework. Go AS. proven quite effective at delivering other CBTs as exemplified by the IVF model [19] . Steril.Autologous cell therapies: challenges in US FDA regulation for failing to live up to FDA investigational new drug application standards. Part A 14(2). and the FDA. N. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. 109(6). USA (2010). Plast. 16 Philippidis A. Star Tribune 13 August (2012).patientsbeyondborders. we must be mindful of the very clear financial conflicts of interest held by industry. www. 12–13 (2012). cuts losses. Nature 466(7309). Deweerd E. FDA challenges stem-cell 4 clinic. Frantz S. How the FDA could cost you your life. http://grailresearch. Nature 488(14) (2012). Tissue Eng. Inc. As we contemplate the structure of new regulatory frameworks. 155–166 (2012). ­ References 1 Lysaght. Tissue Eng.com future science group 97 . 309–320 (2004). FDA warning letter to 5 upheld. 305–315 (2008). 10(1–2). regenerative medicine. Denend L. National Venture Capital Association. Great expectations: private sector activity in tissue engineering. 18(3). Stem-cell experts raise concerns www. No writing assistance was utilized in the production of this manuscript. Ultimately this debate has many parallels with the evolution of organ transplantation. 15 Gottlieb S. State medical boards. VA. in contrast.gov/ICECI/EnforcementActions/ WarningLetters/2012/ucm297245. J. 18 Roger VL. Biotechnol. Tissue Eng.

Kyoto_University_iCeMS_left.pdf 1 2012/10/12 16:07:52 C M Y CM MY CY CMY K hiPSC hESC .

and physics theories of mesoscopic events in materials and living cells.ac.” Fo un ti Deputy Director Susumu Kitagawa on s Physics Stem cells together with mesoscopic sciences. Culture. 3) integration of mesoscopic materials and living cells.” will be held at Kyoto Univ in March 2012. Science and Technology (MEXT) .Kyoto_University_iCeMS_right. entitled “Cell-Material Integration and Biomaterials Science. Director Norio Nakatsuji CiRA* Director & iCeMS PI Shinya Yamanaka Combining physics. simulation. From left: iCeMS Main Building (Research Building located just a block away) | iCeMS faculty and staff at its annual retreat | iCeMS scientists from around the world *Kyoto University Center for iPS Cell Research and Application (CiRA) Ministry of Education. U Edinburgh MRC-CRM Seoul Nat’ l U Biocon Postech-AMS Gifu U Satellite NIH-CRM Purdue U BAMS UCLA-CNSI ce pt C M Y CM Integrated Cell and Material Sciences Cell Biology News & events State U MIPT MPI-CBG Heidelberg U U Cambridge CSCR NCBS/inStem JNCASR s Kyoto U iCeMS Riken-CDB Peking U-Tsinghua U CLS O bj ec ti Collaborating with partner institutions across the globe • The Royal Society of Chemistry and iCeMS launched a new multidisciplinary journal: Biomaterials “Bringing together Science. the molecular and • To commemorate the launch. and 4) creation and application of stem cell-derived disease models. chemistry. 3) control of ES/iPS cell growth and differentiation with chemicals and materials. First advance articles were published online in Sept 2012. pharmaceuticals. Sports. and cell biology. science and technology include: 1) imaging Mesoscopic and probing mesoscopic complexes in living cells. the environment.Univ.pdf 1 2012/10/12 16:11:19 Institute for Integrated Cell-Material Sciences Kyoto University www. 2) i at lic pp A K ey n co s on Stem Cell S&T Mesoscopic S&T production of functional mesoscopic materials (e. an iCeMS-RSC joint symposium. 2) chemical probes for stem cell research.jp | facebook.g.com/Kyoto.kyoto-u.icems. ve MY CY CMY Chemistry da K mesoscopic interactions of biomaterials and their potential applications. porous coordination polymers). and 4) modeling.iCeMS Fusing cell and material sciences Innovations in medicine. Join us at iCeMS in Kyoto to create a new science.. and industry cell science and technology include: 1) reproStem gramming with chemical compounds for iPS cell derivation.


opinion Autologous cell therapies: the importance of regulatory oversight
Michael Werner, Tim Mayleben & Gil Van Bokkelen*
Promising new medical technologies and approaches to treatment offer the potential to substantially improve the lives of patients who need help, and in some cases transform the way medicine is practiced. In recent years, the biotechnology industry has generated many examples of new approaches that are having a profound impact on medical care, including protein and peptide therapeutics, monoclonal antibodies and molecular diagnostics. Many regard the field of cell therapy in regenerative medicine as having transformational potential – capable of substantially improving medical outcomes, enhancing patient (and family) quality-of-life and ultimately reducing overall healthcare costs. Over the past decade, we have seen an explosion in the number of peerreviewed publications exploring the biology of various stem cell populations, and evaluating their use in a range of preclinical disease models. Furthermore, we have seen consistent growth in the number of programs advancing into clinical trials, using both autologous and allogeneic-based cell therapy approaches (Table 1). Despite this, some argue that progress has been slowed by an overly burdensome regulatory framework imposed by the US FDA. While some FDA reforms are needed it is worth remembering that the majority of experimental therapies are ultimately found wanting during clinical trials. In some cases, promising candidate therapies do not actually help patients in a consistent or meaningful manner, or may pose unexpected safety issues that are only identified during the conduct of rigorous clinical studies. Even substances that naturally exist in the human body are not guaranteed to be safe and effective when they are used as therapies. In fact, while biologics have shown a meaningfully better clinical success rate than pharmaceuticals, only a minority of new biologic treatments are ultimately proven to be both safe and effective – approximately one in four, according to the BioMedtracker study results that were released in February 2010. This project, which analyzed over 4275  drug development programs in various stages of clinical development from October 2003 to December 2010, found that approval rates for lead indications among biologics was 26  versus  14% for other new molecular entities (and substantially lower for secondary indications in both categories). Some have argued that a restrictive regulatory landscape in the USA has led many groups to conduct clinical trials internationally, foregoing trials that involve FDA oversight, thereby leading to a severe reduction of domestic clinical activity. However, an analysis of both autologous and allogeneic cell therapy-based approaches demonstrates
ISSN 1746-0751

Few would argue that the regulatory landscape doesn’t need improving, and we must continuously be thinking about ways to make it clearer, more predictable and more efficient, including refining the definitions used to determine regulatory oversight.

Michael Werner, Athersys, Inc., (NASDAQ: ATHX), 3201 Carnegie Avenue, Cleveland 44115-2653, OH, USA Tim Mayleben, Athersys, Inc., (NASDAQ: ATHX), 3201 Carnegie Avenue, Cleveland 44115-2653, OH, USA *Author for correspondence: Gil Van Bokkelen, Chairman & CEO, Athersys, Inc., (NASDAQ: ATHX), 3201 Carnegie Avenue, Cleveland 44115-2653, OH, USA


10.2217/RME.12.90 © 2012 Future Medicine Ltd

Regen. Med. (2012) 7(6 Suppl.), 100–103

Autologous cell therapies: the importance of regulatory oversight

that since 2000, there are a substantial number of FDA-authorized clinical trials using stem cells that involve clinical institutions in the USA, and that the number of such trials has grown over time. While international clinical activity regarding stem cell therapies has also grown substantially, there clearly is no barrier to entry for sponsors who wish to conduct clinical studies in the USA (or in Europe, where the regulatory framework is generally regarded as being similar to that in the USA) (Figure 1). The Center for Biologics Evaluation and Research is the center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. FDA regulations for cell therapies are designed to promote safe collection, manufacture, storage and use of human cells, and cellular- and tissuebased products (HCT/P). These regulations can be found at 21 CFR. Parts 1270 and 1271 (note that The Center for Biologics Evaluation and Research does not regulate the transplantation of vascularized human organ transplants, such as kidney, liver, heart, lung or pancreas). FDA regulations of HCT/Ps include comprehensive requirements to prevent the introduction, transmission and spread of communicable disease. To be exempt from FDA regulatory oversight HCT/Ps must meet criteria set forth in the Public Health Service Act. FDA defines ‘manufacture’ as “any or all steps in the recovery, processing, storage, labeling, packaging or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor”, as described in 21 CFR. 1271(e). To be exempt the HCT/P must be: minimally manipulated; intended for homologous use as reflected by the labeling, advertising or other indications of the manufacturer’s objective intent; not be combined with a drug or device;
future science group

Table 1. Number of clinical trials listed on ClinTrials.gov analyzed by trial start date according to the year of indicated initiation.
Year 2012† 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001

Autologous trials initiated 22 50 47 45 30 34 29 32 23 12 13 12

Allogeneic trials initiated 22 23 12 15 18 10 10 6 5 14 9 17

Numbers for 2012 indicate trials initiated through mid-year. Data from [1].

not have a systemic effect and not be dependent on the metabolic activity of living cells for its primary function except if for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use. Additional components of the FDA’s regulation of HCT/Ps are found at 21 CFR 1271. The concept of what constitutes appropriate regulatory oversight was the central issue in a recent ruling by the United States District Court for the District of Columbia in United States v. Regenerative Sciences LLC. This case raised important questions about the extent of the FDA’s jurisdiction over procedures where autologous cells (a patient’s own cells or tissues) are administered in a physician’s office, clinic or a hospital. At the heart of the argument is whether such treatments are ‘biologic medicines’ (also known as a ‘biologic’ or a ‘biological product’), that should require human clinical trials to demonstrate safety and efficacy and be regulated by FDA. In autologous cell therapy, where cells are isolated from the patient for subsequent readministration to the patient, the FDA has stipulated that in

some circumstances, no clinical trials are required. Specifically, this is the case if the cells or tissue that have been harvested from the patient meet the standard of ‘minimally manipulated’ and the cells are being used in a ‘homologous manner’. For autologous therapies that do not meet the definition of minimally manipulated, and/or that are not being used for a homologous biological purpose, the FDA has deemed it appropriate to require clinical trials to establish safety and efficacy. Key to understanding whether FDA regulations apply are the concepts of ‘minimally manipulated’ and ‘homologous use’. The FDA defines ‘minimal manipulation’ in the following manner: “…[f]or cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues” (see 21 CFR 1271.3(f)(2)). While the FDA has issued some guidance on the minimal manipulation of structural tissue, no such guidance has been issued to define the minimal manipulation of cells. However, in a proposed approach issued in 1997, the Agency stated that “processing of cells and nonstructural tissues to be more-than-minimal manipulation when the processing

Werner, Mayleben & Van Bokkelen

alters the biological characteristics (and thus potentially the function or integrity) of the cells or tissue, or when adequate information does not exist to determine whether the processing will alter the biological characteristics of the cell or tissue. Examples of morethan-minimal manipulation of cells and tissues include cell expansion, encapsulation, activation, or genetic modification” [Docket Number 97N-0068]. FDA regulations define ‘homologous use’ as “the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor” (see 21 C.F.R. 1271.3(c)). The transplantation of hematopoietic stem cells obtained from bone marrow or the peripheral blood for the treatment of leukemia is an example of homologous use, and is a treatment that has been used and studied for more than 40 years.

Some argue that this regulatory treatment of autologous cell therapies may be contrary to good medical practice. They say physicians must be allowed to use their judgment to develop and administer new cell therapies outside of the clinical trial process – similar to other experimental surgical or medical procedures. Clearly, there needs to be some room for investigator-driven innovation in medical practice, and physician-sponsored clinical studies. However, it is also important to ensure that patients are being adequately informed with regard to the true risks and benefits of a potential treatment – especially when they are asked to pay for it. Unfortunately, while in general there is an outstanding record of safety associated with autologous cell therapies, there are a few examples where a patient’s own cells have been readministered for something other than a homologous biological purpose, in which the patient was inadvertently harmed, or even died,

as a result. These types of events could reflect a lack of training or knowledge that could be gained from formal clinical trials, and underscore the need for some form of rigorously controlled studies and regulatory oversight. It should not be assumed that just because the cells are derived from the patient that the approach is perfectly safe, the physician and patient are both adequately informed, and nothing bad can happen. Few would argue that the regulatory landscape doesn’t need improving, and we must continuously be thinking about ways to make it clearer, more predictable and more efficient, including refining the definitions used to determine regulatory oversight. Recent progress should help create a clearer and more efficient regulatory path for sponsors attempting to develop new therapies designed to address significant unmet medical needs. In July, Congress passed and President Obama signed the Federal Drug and



Figure 1. Geographic distribution of clinical trials that have been registered on ClinTrials.gov since January 2000 that are listed as involving stem cells as an interventional part of the therapy. Search criteria exclude gene ­therapy  trials.
102 Regen. Med. (2012) 7(6 Suppl.)
future science group

This legislation included important new provisions intended to speed clinical development in areas of great medical need. The very promise of regenerative medicine illustrates the need for regulation: for where there is promise science provides protection against false hope. The regulatory and clinical trial process is intended to ensure public safety during this time of scientific advancement. all patients are hurt because it slows the field. T Mayleben is CEO at and holds financial interest in Aastrom.Autologous cell therapies: the importance of regulatory oversight Safety Innovation Act. these provisions are likely to greatly facilitate rapid development and commercialization of regenerative medicine and cell therapies. which included a renewal of the Prescription Drug User Fee Act. a law firm that represents numerous companies in the regenerative medicine sector.gov future science group www. so that patients can be helped. Website 1 ClinicalTrials. The best – and fastest – way to achieve that goal is to ensure that cell therapies undergo rigorous testing. especially those with transformational potential. How they are applied will likely change over time as science advances and researchers – and the FDA – learn more about the biological properties of certain cell and tissue based therapies. But companies that promote cell and tissue ‘therapies’ not demonstrated to be safe and effective are really only marketing risk. owns shares in and has options with Athersys. Taken together. But ultimately. delaying the development of safe and effective cures and treatments. Both frameworks are designed to reduce the length. Specifically.gov http://clinicaltrials. while also protecting patient safety. rigorous science will ultimately bring safe and effective products to patients. cost and complexity of clinical trials. When adverse events happen under those conditions. Thoughtful. Current regulations balance protecting public health by requiring data demonstrating that certain uses of cells are safe and effective. reach patients quickly. veneered with unsubstantiated promises. patients need their physicians to have access to numerous safe and effective therapies to treat their disease or condition. Financial & competing interests disclosure G Van Bokkelen is employed as Chairman and CEO by. and the creation of a ‘breakthrough therapies’ category for promising new medicines.com 103 .futuremedicine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. it includes a broadening of the ‘accelerated approval’ pathway. The prospect of new regenerative treatments and even cures where current medicine and therapies offer little hope for the patient is thrilling. No writing assistance was utilized in the production of this manuscript. A rigorous clinical trial system will ensure that safe and effective products. M Werner is a partner at Holland & Knight. Physicians must always be empowered to do whatever they lawfully can and use their best medical judgment to help patients.

The eight large fenestrations in the outer sleeve. 80mm and 105mm lengths. the all-new Bio-MAC is the fastest. 45mm.BiologicTherapies. INNOVATIVE RESEARCH at BRADLEY UNIVERSITY Dr. Ocala.edu 5817 NW 44th Avenue. combined with the void created by the plunger. Craig Cady and his team of student collaborators conduct research using stem cells for regenerative medicine for heart disease and neurodegenerative disease including Parkinson’s disease. The Bio-MAC is available in 25mm. IL 61625 • www.Bone Marrow Aspiration Catheter Inserted with any standard surgical drill.com . FL 34482 352-304-5149 • Fax 352-512-0801 www. Their research efforts are also directed at developing a stem cell-based therapy for ovarian cancer. Trocar & Outer provide 120% Sleeve Assembly more draw area than other similar devices. Call today for more information.bradley. Peoria. gentlest and most efficient bone marrow aspiration catheter Plunger available today.

the FDA makes provisions for treatment investigational new drugs (INDs). autonomy and risk– benefit balance. such as undue influence and the risk of exploitation of vulnerable subjects. Tel. industry. no passage in any of the primary literature cited above addresses the ethics of requiring. and skewing of the risk–benefit balance. respect for persons. In the case of the treatment IND. and in any case such access may only be granted for agents already under investigation in a formally registered trial and with the approval of the trial ISSN 1746-0751 *Author for correspondence: Science Policy and Ethics Studies Unit.75 © 2012 Future Medicine Ltd Regen. scientific challenges that unavoidably confound this approach to the funding and conduct of clinical research. additional guidance documents.2217/RME.riken 10. protection of rights and justice. due to the experimental. These include beneficence/nonmaleficence. This approach to clinical research funding. Fax: +81 78 306 3090. inducing. not-for-profit foundations. philanthropies and charitable and advocacy organizations. In recent history. the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1978) [2] and the International Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences. informed consent. In the USA. including the Declaration of Helsinki (World Medical Association. has been more limited. and thus uncertain. encouraging or allowing patients to pay for their own participation in a clinical research study. (2012) 7(6 Suppl. 1964) [1] . Med. established in 1947. particularly. parallel track studies and various openlabel or open-protocol studies as part of its efforts to allow for ‘expanded access’ to investigational agents prior to the completion of a phased clinical trial.12. while many of these ethical doctrines extensively discuss issues arising from the payment or other forms of compensation of human research subjects. including government agencies. Kobe. potential exacerbation of therapeutic misconception and placebo amplification.: +81 78 306 3043. despite the clear ethical tensions inherent in such an approach to research funding. with reference to its implications for issues. Discussion of the scientific implications of this funding scheme. emergency INDs. autonomy. RIKEN Center for Developmental Biology. nature of investigational agents. There do exist several forms of clinical study in which patients acting as research subjects have been expected to make some financial contribution or payment. has a long and fraught ethical history. Importantly. therapeutic misconception. 650– 0047. 2–2–3 Minatojima Minamimachi. subjects with life-threatening or untreatable diseases may be able to pay to obtain access to investigational drugs that have been shown to have adequate safety and for which data suggestive of efficacy is available [4] . has been both criticized and rationalized on ethical grounds. In subsequent years. 105–111 105 . as outlined in greater detail below. sipp@cdb. however. maintenance of equipoise.POLICY. Keywords: biomedical ethics n clinical research n equipoise n fee-for-service n therapeutic misconception The history of an unusual idea Clinical research. including equipoise. was the first internationally ratified document governing the ethical conduct of human medical research [101] .). justice. I will briefly review the history of the pay-to-participate model in the context of experimental cell and tissue treatments to date and highlight the many ethical and. Japan. Chuo-ku. which include fair subject selection. the US government does not recognize such access as a fundamental right [5] . REGULATION & ETHICS Perspective Pay-to-participate funding schemes in human cell and tissue clinical studies Douglas Sipp* Funding support for clinical research is traditionally obtained from any of several sources. Interestingly. 2002) [3] have expanded on and refined the principles first espoused in the Nuremberg Code. there have also been a limited number of cases in which clinical research programs were established in which funding was provided directly by patients in turn for the ability to participate as nonrandomized subjects. dosage and efficacy in the treatment of specific medical conditions. It may be that in the first decades of biomedical ethics following the promulgation of the Nuremberg Code there was no perceived need to address this situation. which I refer to here as the ‘pay-to-participate’ model. The Nuremberg Code. however. in which experimental interventions are tested in human subjects for properties such as safety.

Also in Tennessee. The FDA conducted an investigation of the proprietor of Solo Research for this practice.Sipp sponsor and regulatory authority. working with academic and industry partners to conduct rigorously designed clinical studies. In these patientsupported funding models.) extensive discussion of this clinical research funding model at the time. This funding model was frequently referred to at the time as ‘fee-for-service’ clinical research. Solo Research. evidently on the grounds that the business did not cross state lines [11] . and there does not appear to be any linkage at the individual level between making a financial contribution and eligibility to participate in a sponsored study. a not-for-profit organization that offered experimental open-label injections of myoblasts to Duchenne’s muscular dystrophy patients [13] . At about the same time. numerous programs in the USA and Mexico conducted research into the use of allogeneic fetal tissue grafts [14] and autologous adrenal medullary transplants [15] in the 1990s. (2012) 7(6 Suppl. and are direct antecedents of businesses that have offered similar pay-to-participate trials in the human cell and tissue therapy arena. The Hospital San Jose Tecnologico de Monterrey. At least one private company. The 1980s saw the advent of several businesses in which the research funding scheme called on patients to pay fixed amounts to ensure their place in generally open-label research programs. It is also important to note that while the primary focus of the clinical trial in such cases continues to be research. Numerous not-for-profit organizations fund and organize research in disease areas of interest. however. but only after several tens of thousands of women had been subjected to this expensive and unnecessary procedure. for which patients are reported to have paid tens of thousands of dollars [16] . at a time when several registered clinical trials of this protocol were still underway [12] . in some cases charging several thousands of dollars for access to patients overseas [102] . Mexico-based organization with an emphasis on medical tourism.’ rather than the broader ‘patient-funded. After entering bankruptcy following the failure of its monoclonal antibodies business. I refer to clinical research funding approaches in which there is a direct relationship between financial payment or donation by an individual patient and the enrolment of that patient in the study in question as ‘payto-participate. CollabRx. specializing in high-dose chemotherapy plus autologous bone marrow transplantation for late-stage breast cancer patients. should more explicitly acknowledge the contributions of human subjects. the Tennesseebased private company Biotherapeutics introduced this novel funding model for what it described as clinical studies into cancer treatments using personalized monoclonal antibodies. Although neither Biotherapeutics nor Solo Research was engaged in transplantation of human cells or tissues. A group of multiple sclerosis patients. for example. the organizations collecting the financial donations and those conducting the clinical research typically remain independent of each other. but was unable to secure sufficient funding to sustain its business model and had effectively ceased operations by 1989 [8] . a separate company in California.’ which could include unproblematic research efforts in which groups of patients provide all or part of the funding for clinical studies in which eligibility is not tied to payment. Similarly. A number of organizations have also conducted ‘fee-for-service’ or ‘patientfunded’ clinical research into stem cellbased treatments for a range of medical conditions. a Monterrey. conducted clinical studies testing peripheral bloodfuture science group . and numerous advocacy groups and foundations have organized funding drives that provide supplementary research funds for target conditions. In 1985. recently funded a study of low-dose naltrexone conducted by clinical scientists at UCSF [6] . whereas the FDA took no action against Biotherapeutics. as it relied on an imported drug (one which in fact later received marketing authorization following testing in a registered clinical trial conducted by a different company) [10] . as they established precedents that triggered Regen. This may be particularly advantageous in supporting clinical research into medical conditions affecting relatively small numbers of patients or involving the use of unpatentable interventions. The company enjoyed some early success in establishing collaborations with scientists at major research universities and institutes. the investigational agent is taken out of that context and for exceptional limited use as a potential treatment. The results of clinical trials revealed that the protocol employed by Response and several other commercial enterprises was no more effective than placebo. Response Oncology. in that any description of research as a ‘service’ (which itself is a debatable conceptualization). began marketing access to an investigational drug for the treatment of Alzheimer’s that had not been approved by the FDA [9] . Other forms of patient-supported research are also known. I have included them here for historic reasons.000 to participate as research subjects. Med. rather than portray them simply as paying consumers. Biotherapeutics was resurrected as a new oncology franchise. Several investigational uses of human cell and tissue products have also been offered to patients on a payto-participate basis. in which patients paid up to US$35. which might otherwise be neglected by industry. For these reasons. neurophysiologist Peter Law established the Cell Therapy Foundation. With 106 the exception of historical contexts. I also avoid the use of ‘fee-for-service’ to describe such funding mechanisms. has been established to provide support and coordination for patient-sponsored clinical research [7] .

visual. the Regenerative Medicine Institute (RMI). including the administration of investigational stem cell products to individuals not enrolled in the IND trials [18] . neurodegenerative. metabolic. and did not comment on the ethicality or viability of the model [24] . Due to space constraints. notably. but again there is no clear record of human research subjects being asked to pay to participate in the clinical trials sponsored by this organization. and the hazards to scientific research. while raising and examining the arguments for and against such an approach. TCA Cellular Therapy. said of Biotherapeutics ‘It’s cruel deception.000 (data archived by author). In one published comment. on an ad hoc basis. and economic biases in enrolment and interpretation of results [20] . I will only summarize their conclusions here. a report issued in 1987 by the US government Office for Technology Assessment (‘New Developments in Biotechnology: Ownership of Human Tissues and Cells’ noted the recent emergence of the ‘fee-for-service’ clinical research funding model. One website associated with the RMI.107] . autoimmune. in which the author addresses and for the most part dismisses the threats posed to patients.’ such as the assessment of disease prevention by dietary supplements. orthopedic. Evans and Block looked specifically at the ethical issues in patient-funded clinical research in the context of ‘complementary medicine. renal. and. highlighting the concerns of several researchers that the pay-to-participate scheme would affect quality of the research design. Arnold Relman. At least one US-based company. has introduced ‘patient-funded clinical trials’ of various stem cell interventions. 107 . inequalities in access and risk of patient exploitation [25] .futuremedicine. it should be pointed out that Oldham was also the founder of Biotherapeutics.’ [11] . It’s commercial exploitation of a tragedy.000 (it was possible. however. it is important in such cases to account and control for the introduction of risks and biases due to the pay-to-participate study design. The most comprehensive analysis to date of the arguments for and against patientfunded research appears to be that by Morreim. citing individual freedom to choose and ethical equivalence with industryfunded clinical studies in defense of the already controversial funding scheme. specifically including psychological risks to the patient-subjects. vascular. a novel treatment when no standard therapies are available that might reasonably be offered to a patient’). Lind suggested that while it may be appropriate to ask patients to pay for ‘informal’ studies (which he defined as those in which ‘a physician uses. In addition to these two clinical organizations in Mexico. the risk of inequalities in opportunity to participate for financial reasons. Several of these have also registered clinical trials with various authorities subsequent to treating large numbers of patients [106. In an earlier commentary. as indicated in descriptions such as ‘Here at Angeles Health we offer patient funded stem cell therapy trials for COPD. www. for prospective subjects to waive the contribution if they were unable to pay) [103] . concluding that ‘it may be quite appropriate to permit patient-funded research’ provided that appropriate standards are in place to ensure similar levels of scientific quality and patient safety to those observed in research funded by traditional means [22] . Lind briefly noted the establishment of a company (Biotherapeutics) that had begun marketing ‘fee-for-service’ research into individualized monoclonal antibodies for cancer treatment. and hematologic conditions. I think it’s totally immoral. an editor of The New England Journal of Medicine. but focused primarily on ownership of human biological materials in this context. heart conditions and many other health problems’ [104] . in which patients were encouraged to subsidize the research through financial donations of up to US$18. for which costs ranged from US$7500–35. Robert Oldham published a rationale in favor of ‘fee-forservice’ research in the cancer context. suggested that ‘criteria for approving a patient-funded trial should be more stringent than those applied to the usual sorts of clinical trials’ [19] . rather than research. an organization affiliated with Angeles Hospital International in Tijuana. as well as for various cancers. lung. This is not to suggest that the payto-participate funding model has not occasioned controversy as well. which lies at the heart of therapeutic misconception. was sent a warning letter by future science group the FDA for a host of protocol violations in the conduct of registered IND studies. and concluded that ‘a strong ethical case may be made for the appropriateness and value of significantly expanded fee-for-servicesfunded research’ in such contexts [23] .com the company many cite as the first to introduce this funding model [21] . but I have been unable to determine whether in these cases patients were asked to participate in such trials. in which individual patients are asked to pay thousands of dollars to participate as subjects in open-label studies of stem cells for a wide range of medical conditions. Scientific validity & ethical principles Several analyses of the ethics of payto-participate clinical research have been published to date.Pay-to-participate funding schemes in human cell & tissue clinical studies derived CD133 + cells for the treatment of amyotrophic lateral sclerosis [17] . but I do so with strong encouragement to interested readers to seek out and compare the articles cited. Lastly. Also in Mexico. the very phrase “stem cell therapy trials” is highly suggestive of a conflation of research with care. a large number of companies have advertised ‘experimental’ stem cell interventions in which the primary emphasis was more clearly on patient care. StemCellMX [105] until recently featured a menu of experimental stem cell treatment options for heart. The New York Times published a lengthy article on the same company.

The International Ethical Guidelines for Biomedical Research Involving Human Subjects. along with more traditional values such as beneficence.Sipp As we can see from the above. Appropriate design measures. Med. preliminary forms of research. as bona fide stem cells may survive and continue to function for the life of the recipient. as it seems intuitively clear that many patients would object to paying large sums to participate in studies in which they were subject to the uncertainties introduced by such standard experimental design 108 features as randomization and blinding. and allowed patients to seek exemptions based on financial need. and indeed of the intervention under study. as described in detail below [21. however. or simply due to the sense of investment felt by research subjects. While it might be argued that placebo effects associated with the perceived advanced nature of the technology under investigation. lack of funding alternatives and substantial equivalency with other forms of research funding in support of their positions. Some approaches. that value associations. could bias the results of such studies toward greater efficacy than might be observed in the general population. and included views voiced by prominent ethicists that were critical of the pay-to-participate model. Notably. What then does this mean for pay-to-participate funding mechanisms? The first set of scientific issues center on experimental design. particularly when these involve payments of tens of thousands of dollars. In my view. respect and justice. One recent report of value influences on placebo effects showed that even small differences in the perceived monetary value of otherwise identical inactive placebos resulted in significant differences in the pain relief reported by test subjects. is an issue in many studies. and registered clinical trials of novel stem cell interventions typically include follow-up periods future science group . or exclusion of less healthy ones. there are potential issues in recruitment or selection bias for studies funded in this manner as well. these critical views. thus rendering themselves unable or ineligible to participate in such studies due to lack of funds. given that more seriously ill patients may have exhausted their savings. with those who were told that they were receiving (placebo) pills of supposedly higher value reporting greater relief [27] . have made donations voluntary. the scientific implications of the pay-to-participate funding model have yet to be discussed adequately.) as the very act of paying is likely to establish a notion of the ‘value’ of the opportunity to participate. would tend to skew the results of any research funded directly by study participants. I have chosen to highlight some of the more salient issues below. for example. This inherent incompatibility between standard experimental controls and the pay-to-participate model would appear to make this funding mechanism only appropriate for less rigorous. It should also be noted as well that media reports from the time noted significant ethical controversies. That distinction notwithstanding. such effects of value perception on expectation is well documented in numerous other areas as well [28] . but information on such allowances in similar commercially oriented research programs is scant. there has been significant discussion and indeed support on the part of several previous commentators for the notion that clinical research can in certain cases justifiably be funded directly by patients seeking to participate as subjects. It appears. Prescriptive approaches to the ethics of clinical research have placed increasing emphasis on the primary importance of scientific validity [26] . laissez-faire regulation on the part of the government. Conversely. (2012) 7(6 Suppl. such as the study of a stem cell treatment for amyotrophic lateral sclerosis at Tec de Monterrey. and as these have important consequences for the ethical viability of the model. Such effectively selective inclusion of healthier subjects. raising legitimate questions about their scientific value. such as comparison against an otherwise identical nonpaying arm. the additional requirement to pay large sums of money is likely to have an additive effect in such cases.22] . however. Those expressing positive views have typically emphasized concepts of individual freedom to choose and ability to consent. however. exacerbating any underlying predisposition to placebo responses due to other causes. do not appear to have been developed into peer-reviewed publications. Regen. the need for long-term surveillance must be confronted in any funding model. The Guidelines for the Clinical Translation of Stem Cells published by the International Society for Stem Cell Research specifically recommends that human research subjects should be monitored for long-term health effects [29] . such as open-label and individual case studies. or may use their greater resources to obtain a greater variety or quality of co-interventions than less wealthy patients. patients with the financial ability to pay may represent a healthier population than those with more severe illness. rather than the basis of a business model in which continued recruitment of paying patients is a primary revenue source. may be necessary to exclude such potentially confounding factors. specifically states that ‘scientifically invalid research is unethical in that it exposes research subjects to risks without possible benefit’ [3] . therefore. In human cell and tissue trans­ plantation particularly that involving stem cells. and several analyses have raised specific justifications for studies in which ability to pay is an inclusion criterion. The pay-to-participate model may have serious consequences on the interpretation of results as well. open-label studies are generally conducted in academic settings and represent a first step toward more rigorously controlled research.

Indeed. 109 . motivation. which the investigator does not face in any case. human subjects are frequently compensated by free access to healthcare during the study period. which may return additional value to both subjects and sponsors in the event it is shown to be safe and efficacious. the reasoning being that if the community were certain about the efficacy of an intervention. In the payto-participate model.com from exploitative charlatanism. by giving informed consent. The confusion of research for patient care is a fundamental concern in the ethics of human subjects research. In most traditional forms of clinical research funding. subjects must not only pay upfront and. it would be unethical not to provide it as therapy. Another major consequence of the pay-to-participate research funding model is its skewing of the delicate risk– benefit balance inexorably in favor of the investigator (particularly so when the investigator stands to benefit financially from the enrolment of paying subjects) and against the research subjects. Notably. Clinical equipoise describes the expectation that there be a state of uncertainty on the part of the expert medical community regarding the efficacy or lack thereof of an intervention under investigation [30] . Research in which investigators require patients to pay to participate as subjects by necessity walks a tightrope over this divide. It should be noted that here are certainly cases of open-label studies in which the primary intent is patient care. many of which describe their products and services as ‘experimental. Similarly. in which systematic outcome and other data are collected secondarily. Investigators and trial sponsors stand to benefit from access to healthy volunteers or patients meeting the study criteria. overinterpret neutral ones or overlook neutral ones additional to the potential investigator biases resulting from other nonfinancial causes that are inherent in other research studies. the maintenance of clinical equipoise and the avoidance of therapeutic misconception are two primary concerns. there would seem to be an unavoidable risk of therapeutic misconception. differentiation. but these differ qualitatively from business models in which patients are recruited through marketing efforts to pay to participate in so-called clinical trials or studies. as it may inappropriately affect decisionmaking. this issue is even more problematic in the greater context of the underregulated global industry engaged in the marketing of scientifically unsupported stem cell interventions. an examination of present-day websites advertising ‘patient-funded clinical trials’ reveals that research and therapeutic terms are often used interchangeably. Of the nonscientific ethical issues confronting pay-to-participate clinical research funding. and patient testimonials are provided via prominent links on the same webpage. Inappropriate suggestion of therapeutic intent has been shown to be more commonplace in descriptions of stem cell clinical trials than in trials of other modalities. however. Notably. in which research aimed at developing generalizable knowledge is confused for treatment intended for the care of the individual patient [31. such incautious use of language would appear to make therapeutic misconception an inevitability.’ while providing no information on the nature of the supposed experiment being conducted. From the publicly available information on the pay-to-participate research programs described above. if not a specifically desired outcome. migration and paracrine effects even after long periods of quiescence in vivo. as described above. it does not appear that any have explicitly provided for such long-term follow-up. This warping of equipoise may be further complicated if the participation fee includes a margin for profit on the part of the investigator.futuremedicine. as this could result in conscious or unconscious incentives to emphasize positive outcomes. this voluntary participation provides the sponsor with opportunity to study the investigational agent under controlled conditions. however. been shut down by regulatory authorities or otherwise discontinued their research in these areas.Pay-to-participate funding schemes in human cell & tissue clinical studies of a decade or more. suggesting to both the physician-investigator and the patient-subjects that there is some inherent value in participation (which could presumably be confused quite easily for advance access to medical care). in that investigators are required to assign a monetary value to the act of participation in the study on the part of subjects. highlighting the importance of lengthy and vigilant monitoring in protocols involving living cellular agents that may be capable of proliferation. indicating that the field may be particularly susceptible to such conflation. expectation and perception on the part of subjects. disavow any expectation of efficacy – all of which minimizes the investigators’ financial risks – the subjects must also assume all the physical risks inevitably associated with participation in a research study. Such misleading language presumably makes it more difficult for patients to distinguish actual research www. which appears future science group to have been the case in many of the companies that have conducted payto-participate human subject research.32] . the majority of the organizations that have conducted such research using human cells or tissues in the past three decades have gone bankrupt. when combined with the demand for payment. or even by financial payments to compensate for physical risks or lost time. Conclusion There have been attempts to implement pay-to-participate funding models for clinical research by various commercial and noncommercial entities for the past three decades. but overlooked. suggesting that the financial viability and sustainability of such business models are important. issues.

 Engl. 68(2). Treatment Use of Investigational Drugs – Information Sheet. This attenuation of scientific rigor has important secondary effects on the fundamental ethicality of studies funded in this way. 24 Office of Technology Assessment: New 7 By Failure of Fetal Cell Implants. United States Court of Appeals. Fee-for-service research. Med. legal. Can patients be asked to pay for 4 Transplantation for Breast Cancer. Oxford University Press. Acknowledgments I would like to thank L Turner at the University of Minnesota for critical reading and discussion of an earlier version of the manuscript. 17–23 (2002). International ethical guidelines for biomedical research involving human subjects. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. 697–702 (2001). Caro E. Letter TCA Cellular Therapy. 21 Oldham RK. Kornyeyeva E. 84–87 (1990). ƒƒ Scientific problems arise from difficulties with experimental controls. J. von Eschenbach. Wall Street Journal. 7(6). Doctor in Mexico Defends His paying the piper or protecting the patient? IRB 13(3).Sipp a surprising number of which have focused on human cell or tissue transplantation. ƒƒ Particular ethical problems associated with this funding model include the disturbance of equipoise and the likely conflation of research with medical care (therapeutic misconception). Alzheimer’s study. GutierrezJimenez E. Med. 472–474 (1992). J. Abigail Alliance v. N. N. Biotherapeutics: expensive 19 Lind SE. but also severely constrain the scientific validity of the investigation. Segura JJ. Given the many profound and often disturbing implications of pay-to-participate funding mechanisms for research design. Ann. 20 Lind SE. District of Columbia Circuit decision (2007). 110 Regen. 17 9 2 Martinez HR. Med. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Ethics (182). in both scientific and financial terms. Oxford. implementation and analysis. 46–47 (1987). August 30 1988. DC. Moreno-Cuevas JE. ethical. Neurol. Ethics. consultation. blinding and placebo amplification. August 15 2011. 22 Morreim EH. ƒƒ The pay-to-participate funding model has numerous and profound scientific and ethical implications for study design. The difficulties in experimental design introduced by requiring subjects to pay may not only limit enrolment. Block JB. Food and Drug Administration. Cree BA. New York Times. Aust. N. stock ownership or options. Goverment Printing Office. randomization. 316(1). a number of organizations have engaged in clinical research in which patients were asked to pay to participate as subjects.) future science group . No writing assistance was utilized in the production of this manuscript. Ethical issues regarding 6 15 Rosenfeld JV. 180(12). Natl Cancer. Probe turns up flaws in 18 Food and Drug Administration: Warning 3 11 Raeburn P. No authors listed. or equal opportunity? The Scientist 2(24) (1988). March 1987. Marcus AD. New York. 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XX © 2011 Future Medicine Ltd Regen.XX. Med. (2011) 6(5 Suppl.2217/RME.).ADVOCACY & EDUCATION ADVOCACY & EDUCATION Article type Interviews The making of an advocate Alan Fernandez The New York Stem Cell Foundation Susan Solomon Commentary Why the stem cell sector must engage with social media Lee Buckler 10. xxx–113 ISSN 1746-0751 113 .

Steve and Barbara Beyer carry the spirit of their late son.). how can we stand back and let a group with a minority position impose their will on the majority? “ ” 114 10. In building the network of supporting organizations and sponsors for that meeting. Associate Director at the Genetics Policy Institute (GPI). to find out what led him to devote his career to stem cell advocacy. with the goal of changing lives for the better. Where we have an emerging field of stem cells and regenerative medicine that could possibly cure previously untreatable diseases. GPI’s Executive Director. Ben. Where we have an emerging field … that could possibly cure previously untreatable diseases. My good friend here in Palo Alto is Gary Dawson. Med. I felt firsthand that extreme sense of urgency. a wonderful grassroots organization.2217/RME. (2012) 7(6 Suppl. was obviously a ‘man on a mission’ and from that Summit in Boston. how can we stand back and let a group with a minority position impose their will on the majority? Where is the collective compassion for the suffering and chronically sick? I decided that I could best live up to my potential and have a better life dedicated to stem cell advocacy. Q How did you come to join the Genetics Policy Institute? I started working with the GPI while I was at Burrill Life Sciences Media Group. who deals with immense physical challenges resulting from cerebral palsy.89 © 2012 Future Medicine Ltd Regen. The Beyers created ALS Worldwide. The Hempel family who created the Addi & Cassi Fund with their precious daughters afflicted with childhood Alzheimer’s disease. whose bravery battling amyotrophic lateral sclerosis was memorialized in a documentary. Bernie Siegel. Where do get your inspiration to be a stem cell advocate? Dealing with those individuals and their family members afflicted with chronic disease offers me continuing inspiration. counseling families dealing with that horrible affliction.ADVOCACY & EDUCATION Interview The making of an advocate Interview with Alan Fernandez We spoke with Alan. I decided to shift my career focus to nonprofit advocacy. In this journey. Burrill was partnering the Stem Cell Summit produced by the GPI with the Harvard Stem Cell Institute in 2007. There are a hundred more.12. I have encountered some really compelling people. 114–116 ISSN 1746-0751 . the organizer of the annual World Stem Cell Summit.

the combined force can move mountains. USA) at the behest of a very brave patient advocate.futuremedicine. Those are motivating factors. the road will be much longer and tougher for all. I developed an interest early on in business. Advocacy is a participatory sport. working for start-ups and mid-sized companies. I started my career as an intern for Drexel Burham Lambert in their London (UK) office. Joan Snyder. It has been a fascinating journey. foreign countries. sponsors. Austria. I traveled to Peoria. People do things when they become emotionally charged and when they feel threatened that something important is about to be taken away. not a cerebral exercise. including the emerging cell therapy companies. Organized by GPI. Last year. not a cerebral exercise. What is one of our your proudest moments? I started at the GPI as Director of Public Policy Outreach and was promoted to Associate Director in 2011. The Coalition is grassroots activism at its best. diverse scientific and medical societies. who runs the Central Illinois Parkinson’s group. How can patients and industry combine to solve problems and advance the field of regenerative medicine? Let’s have some clarity. He then joined the GPI full-time in 2008. Working with patients. the UK and the USA. People do things when they become emotionally charged and when they feel threatened that something important is about to be taken away. forging innovative 115 ” . Explain the role of the Stem Cell Action Coalition. he began working with the Genetics Policy Institute (GPI) on the 2007 Stem Cell Summit with the Harvard Stem Cell Institute. the GPI builds the World Stem Cell Summit from scratch and recruits organizing partners. Earlier in his career. I spoke to the audience about the need to build a powerful movement to address the obstacles facing our field. The Coalition emerged as an important force in 2010 with the threat of the ‘Sherley versus Sebelius’ court case.com releases and frequent policy calls with grassroots activists. While working with Burrill & Company. Without the passion and sense of urgency of the patient community behind them. policy. (IL. born in Chile and growing up in Romania. need to deal with financial and regulatory hurdles. I am the son of an American diplomat. some 250 in number. medical philanthropies. The Stem Cell Action Coalition springs from the Stem Cell Action Network.The making of an advocate Alan has focused his career on advancing stem cell sciences and the field of regenerative medicine since 2006. But it is when speaking with fellow advocates I feel that I have truly found my voice. lived and worked in New York City and eventually migrated to the Bay Area in California. The healthcare industry. press www. leadership and communications. Alan’s skills in business development and marketing were cultivated at companies like Dow Jones. Advocacy is a participatory sport. the Coalition serves as a voice for the stem cell community and as an engine promoting the field of embryonic stem cell research at the federal and state level. The GPI has built a prominent coalition supporting embryonic stem cell research. the coalition includes 75  organizations. Ziff Davis and Burrill & Company. who see the future of regenerative medicine as salvation. Alan worked in technology and grassroots business communications. by changing laws. a group of grassroots stem cell activists present at the creation of the policy battles in 2002. endorsing organizations and media partners from around the world. It’s about commitment to taking action and then taking action. economics. university programs and patient groups. government. circling the globe promoting support for our field. In certain ways we are diplomats. Through letters of lawmakers. You are known for being an ‘international man’: how does your background impact your work? Each year. social media. Switzerland. My role expanded to traveling to a number of future science group “ scientific and industry conferences. I know I have found my voice and my calling. The ovation that day meant the world to me.

Neuhuber. C.com/cto S. Vic. Atlanta.W. Göttingen Tumor Cell Plasticity E. Freiburg i. Ga. You often speak about the importance of music in stirring the soul of an activist. Karger AG Medical and Scientific Publishers P. stock ownership or options. No writing assistance was utilized in the ­ production of this manuscript. Vic. Newgreen. or royalties. and in vitro systems n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro Cells Tissues Organs Editors-in-Chief H. A. If not for ourselves. There has to be continuing communication and interaction and a broad recognition that we are one community. Calif. Würzburg F. honoraria. Badylak. Pa. Salzburg L. Bellamkonda. Ratcliffe.Fernandez collaborations and increasing public awareness. stem cell research. expert testimony. Gatersleben KI12301_cmyk . Müller. Associate Editors Developmental Biology D. How does music move you? Consider a rock concert with 10. Denker. Pittsburg. let’s make it happen for our kids. Viebahn. A few of our friends seem to forget that one day we will all be touched in some way by a chronic disease – statistics show one in three will be afflicted. Music does stir the soul.M. Thompson. Gallo. Melbourne. tissue engineering. our friends and humanity at large.-W. ” Journal of cell and developmental biology. consultancies. Melbourne.M. San Diego.E. Atlanta.000 attendees all dancing to the music. This includes employment. “ Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.karger. all with their arms outstretched holding aloft a flame.Br. English. I grew up moved by the music of Simon & Garfunkel and John Denver and many others. Essen A. Neurosciences R. Toronto.O. My favorite is ‘The Eagle and The Hawk. New Haven. Shoichet. Niklason. L. Ga. Box 4009 Basel (Switzerland) www. W. Eckstein. M. Come dance with the west wind and touch on the mountain tops Sail over the canyons and up to the stars And reach for the heavens and hope for the future And all that we can be and not what we are. Ont. Wobus. grants or patents received or pending. A. 196 6 issues per volume ISSN 1422–6405 (print) ISSN 1422–6421 (online) Functional Anatomy and Stem Cells and Tissue Engineering Biomechanics S. Erlangen M. Frotscher. We are sitting on technologies that may alleviate a huge amount of suffering for adults and children.com Cells Tissues Organs 2012: Volumes 195. www.L. Conn.karger.F.’ Every time I listen to it I am energized. Zurich A.

Susan received a New York State Women of Excellence Award from the Governor of New York.). Susan is a founding member and current President of New Yorkers for the Advancement of Medical Research. Susan.com and was President of Sony Worldwide Networks. The insulin is better. Susan L Solomon is Chief Executive Officer and Co-Founder of The New York Stem Cell Foundation (NYSCF). to discuss the role of the Foundation in facilitating some of the top advances in stem cell science in recent years. (2012) 7(6 Suppl. but when you have end-stage congestive heart failure. I have a son. cultural institutions. a nonprofit organization established in 2005 to accelerate cures through stem cell research. we are basically dealing with the same paradigm: the treatment of Type 1 diabetes is the same treatment that was developed when Banting and Best discovered insulin in the 1920s. an attorney. A series of events in my personal life gave me a heightened awareness of these issues. is on the Executive Committee for the Alliance for Regenerative Medicine. you do not have good options. Prior to founding NYSCF. She established and ran Solomon Partners LLC to provide strategic management consulting to corporations. She was the founding Chief Executive Officer of Sothebys. In March 2008. when you have lung cancer. foundations and nonprofit organizations. Susan was also a member of the Strategic Planning Committee of the Empire State Stem Cell Board. She has also held executive positions at MacAndrews and Forbes Holdings and MMG Patricof and Co. and she has been a member of the Board of Directors of the Juvenile Diabetes Research Foundation.ADVOCACY & EDUCATION interview The New York Stem Cell Foundation Interview with Susan Solomon We caught up with Susan Solomon. Q What led you to the decision to co-found the New York Stem Cell Foundation in 2005? I have been involved in medical research advocacy for a long time. you do not have good options. but we are still dealing with the same paradigm. and the ISSN 1746-0751 10. Co-Founder of The New York Stem Cell Foundation. with Type 1 diabetes and I had lost my parents to heart disease and cancer.2217/RME. The decision to start The New York Stem Cell Foundation (NYSCF) was based on two things: erratic government support for the most advanced research in the USA and seeing that there really was a giant gap between the work being done at academic institutions. New York Chapter. now grown. Med. Going through those experiences I saw first hand that while medicine has advanced over the years. A longtime healthcare advocate. 117–119 117 . she received the Triumph Award from the Brooke Ellison Foundation for her work in establishing NYSCF. With cancer and heart disease substantial progress has been made. spent much of her career building businesses. the delivery method is better.92 © 2012 Future Medicine Ltd Regen. In September 2008. Our understanding of disease is something that until the advent of stem cell research had remained very much a black box.12.

What are the main priorities of NYSCF? When we started in 2005. providing a forum for researchers to discuss their work. high-risk research: Regen. We are now onto our seventh conference in October 2012. and providing the physical facilities and funding to enable research to move forward. so that when a public opinion and public funding is available then that work can be scaled up. One clear problem was that because of funding policies in the USA at the time. And a critical priority was to have a state-of-the-art. who have invented an entirely new field. “ We. like Ed Boyden at MIT. and our principal supporter is the Robertson Foundation. so that they could be encouraged to go into the field. to host an annual meeting for translational stem cell research. We support them for 5 years. as quickly as we could. give them ways to collaborate. With the Investigator program we support early career investigators within 5 years of completing their postdoctoral training and starting their own laboratory. We partner with all of the research institutions in New York City. and the kind of work that we encourage is high-risk. It is the kind of thing that might not work. So we thought it was very important to establish a wellsupported community. Another priority was to ‘bang a drum loudly’. but if it does. which allows us to preserve the culture of the meeting. The laboratory has evolved from what was originally a small but important laboratory. This program is now in its seventh year and we have a network of 35 researchers at universities all over the world. highreturn. When you have future science group …a critical priority was to have a stateof-the-art. and it is really an extraordinary group. “ ” 118 . resources. Med. young researchers were discouraged from going into the field. That is. and providing the physical facilities and funding to enable research to move forward. you are going to have to be rigorous in your approach. We have investigators. The three key priorities we identified were getting young researchers into the field. It is a very generous award. We cover a range of diseases each year and offer an opportunity to highlight those researchers who are doing the most exciting work. US$1. and support from top people in the field. fellowship programs and a laboratory. privately funded laboratory where you could check politics at the door and do the most advanced work. To achieve that we set up the NYSCF Fellowship program. as a small organization. This has created a vibrant community and we now have 45 researchers employed by NYSCF. What became clear is that now that we have young people in the field. to now one of the largest stem cell research laboratories out there. The three key priorities we identified were getting young researchers into the field. real superstars in innovative research. privately funded laboratory where you could check politics at the door and do the most advanced work.) ” research that needs to be done and that the traditional funding bodies simply do not fund. and lead research. From the start we have been doing very exciting work.5 million. If you are going to try something that is risky. providing a forum for researchers to discuss their work. We wanted to help early postdoctoral researchers: fund them. we worked very closely with our scientific advisory boards to identify what we thought were the absolutely critical programs that needed to be established in order for this new field to move forward. it will change everybody’s world. (2012) 7(6 Suppl.Solomon delivery of pills and treatments on the commercial side. could never provide the funding that the government can. We are providing the proof of concept. many times that. We have gone from 500 ft2 to many. they wanted to be able to continue with high-return. But what we can do is create a path. The program has been such a success that 3 years ago we decided to expand it. a small meeting where people could present their work prepublication and share their work with senior researchers. So we established the NYSCF Investigator program as a follow-up to the NYSCF Fellowship program. They consider each other their best scientific friends.

who are going to be starting clinical trials in patients with macular degeneration in the UK at the end of this year. compared to say bone marrow transplants. That has never been done before and was greeted with international acclaim. expert testimony. which industrializes the production of stem cell lines. future science group www. including being named the number one medical breakthrough by Time magazine. So we think it is extremely important to map out a plan for each one of the diseases where we are trying to accelerate treatments. stock ownership or options. That could be really detrimental to the field. If you look at how young this field is. consultancies. honoraria. This is going to be critical for moving to translation. I think our challenge is to make sure that an excellent standard is maintained and that as people see an opportunity in this field we don’t end up with unproven therapies and stem cell tourism. we have already started doing translational work and as the field matures. any road will take you there.com 119 . the laboratory has grown hugely and become a much larger part of our program. and I think we are going to see a real on rush on that.The New York Stem Cell Foundation exciting work going on. much sooner at much less cost. safer drugs and treatment. you are going to see us move much more into translational work. It is an extremely optimistic place. One of the things we are focusing on is the new technology that we have developed. last year our researchers successfully reprogrammed an adult skin cell into an embryonic stem cell through nuclear transfer. with Pfizer. What is it that attracts researchers to this laboratory? Scientists gravitate to where the top research is being done. For example. we are cooperating with Pete Coffey and the London Project to Cure Blindness. I think that the field is doing extremely well.futuremedicine. Work from our laboratory has been cited three times in the last 5 years as the top medical or scientific research breakthrough of the year. or royalties. Where does NYSCF plan to focus its efforts over the next 5 years? We see the NYSCF Research Institute as a key technology partner. it attracts more exciting work and more exciting people. For example. What do you see as the main challenges to translation of stem cells into regular clinical use? I think that is a question of time. No writing assistance was utilized in the production of this manuscript. grants or patents received or pending. The main focus of research at NYSCF is on preclinical work: what was the rationale for that? You have to take a look at where the field is. But we are already seeing drugs that have been pre-screened using stem cell-derived disease models entering clinical trials. consequently. If you don’t know where you are going. and also given the political scrutiny. the NYSCF Global Stem Cell Array. The NYSCF laboratory has doubled in size three times since opening. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. to both academic researchers and industry. This includes employment. However. bridging that huge gap between what goes on in an academic research laboratory and the end goal of better.

celltherapygroup. it will seem similarly ridiculous for professionals. increase your profile and establish influence over a wider network. if you are gleaning all of your information from paper publications (or even their digital versions). To optimize success. your career needs it. Cell Therapy Group. Think of what you say on social media as a conversation. I was asked to present to the management committee the case for why the firm should have a website and perhaps even consider implementing email. it is your career. It involves listening. (2012) 7(6 Suppl. Social media is not the only way to build a profile but it can be very effective.12. Med. not a message. I don’t need social media. For those doing it right and reaping the three above-stated rewards. ƒƒ Enhanced profile: higher profile within your industry. a faster stream of incoming data and/or pandering to one’s ego? Here is the trick with social media. they peer punish. they will often penalize you for inappropriate behavior. your information input is outdated and limited to such an extent that unless you have plans to retire in the next 5 years your career will suffer real consequences.ADVOCACY & EDUCATION Commentary Why the stem cell sector must engage with social media Lee Buckler* In 1995. For those using social media wrong. It was not an easy sell. You will feel the pain if you try to have a one-sided conversation about yourself because not only will people ‘hang-up’ (unfollow). you’re doing it wrong. It enjoys irony. specialty and community. it is critical to communications but it is not a news feed. ISSN 1746-0751 120 10. Even more importantly. If you’re using social media like radio. I can tell you without the slightest hesitation of conviction – having experienced it myself and seen it repeated countless times – active and successful social media engagement translates into: ƒƒ Unparalleled learning: accessing more information relevant to your discipline. their megaphone and ego is not tolerated and it simply does not translate into more influence or a wider network.’ You are wrong. if the extent of your networking is people you meet in real life. ƒƒ Wider network: more touch points and meaningful relationships with people than you otherwise will accomplish by any other means combined (Figure 1). Undoubtedly because of my incessant whining on the matter. profession. In the figurative blink of any eye (and literally within 3 years) websites and email were considered an absolute essential to even the most wrinkled partner with a dictaphone glued to their thumb. 120–123 . it will backfire. specialty and company than you otherwise will. sharing and conversing. is that all social media is about? Is it really just about a louder megaphone. I was a first-year associate in a downtown law firm excited to be invited to my first firm retreat. Not only would your career benefit from your use of social media.95 © 2012 Future Medicine Ltd Regen. best limited to personal rather than business use. www.2217/RME. We are just barely beyond similar days in terms of social media acceptance. If you do employ social media to enhance your knowledge base. Social media is still considered by many to be a tool of frivolity. If you use it primarily to increase your profile. The case for social media engagement You may be thinking ‘I am a serious professional. Social networks do more than peer review. It is a telephone. your career will lag behind those people building virtual networks. Certainly nothing could be further from the truth and in less than the blink it took for the commercial world to accept websites and email. or perhaps at best only of real commercial utility in business-to-consumer applications. In addition. measurable benefits for your career and organization or company? *Author for correspondence: Lee Buckler.com Benefits for your career It is your company or organization. what are the real. academics and companies to operate and succeed without actively using social media. Even as the most highly specialized and cloistered academic.). managing these now means managing them online. It is an important pillar of marketing but it is not advertising.

increased traffic equals increased opportunity to call readers/viewers to your intended action – interaction. “That statistic crushes my heart” [3] . For individual professionals. For individual professionals. Deevy Bishop. USA has been successful in leveraging a LinkedIn group and website into a virtual networking organization (with over 7000 LinkedIn group members) that also holds outstanding. faculty. „„Revenue/income This is about translating a broader knowledge base and a wider network over which you have some level of influence (if only just that they are listening) into more money for your company. employees. joint ventures.info. For companies. For organizations this means finding the right donors.” „„Collaboration There is an intrinsic correlation between one’s profile and the opportunities one has for collaboration. management and so on. a biotechnology consultant (see Comprendia. Alexey Bresenev. is one of the few stem cell research professors regularly blogging. “Only 18% of Americans can name a living scientist” she claims.futuremedicine.org) Mary Canady. I’d been directed to two new papers in my field that were very relevant to my work and that I hadn’t known about. associate professor at UC Davis and blogger at iPScell. With the San Diego Biotechnology Network (SDBN. Communicating your work to the public In a great five-part series earlier this year on the Scientific American blog called Social Media for Scientists. Influence Paul Knoepfler. As Paul Knoepfler wrote in a comment for Nature News: “Savvy scientists must increasingly engage with blogs and social media… Even if you choose not to blog. publications etc. For companies. So there it is – blog or be blogged. In a recent blog post. strategic alliances. Professor of Developmental Neuropsychology at Oxford. states “When I first joined up I was impressed to find that within the first few days. etc. impressing the right grant reviewers and/or recruiting the right rain-maker faculty. write or collaborate in other ways. In a June 2012 blog post entitled ‘Why Scientists Should Publicize Their Findings – for Purely Selfish Reasons’ on the Scientific American Blog. directly attributes finding his current job to the contacts and impressions made as a result of his blogging efforts. blogger at StemCellAssays. program officers notice ” [2] . Professor of Developmental Neuropsychology at Oxford. “Right now. citation. 121 future science group www. Matt Shipman states: “There’s a reason that most grant proposals include a section asking how you plan to disseminate your findings. collaborators. Yes. For companies this means finding the right partnerships. employees and interns.com and CellTrials.” [1] Network Recent postdoc. Christie Wilcox makes a compelling case for why scientists should and must engage in social media activity. As such he is increasingly interviewed as a representative of the sector. engagement. organization and yourself. Case studies Learning In a great blog post advocating Twitter for academics. Most federally funded agencies want the public to know about the work they are supporting. Deevy Bishop. She begins by making the case that science has an image problem – a lack of it and the wrong kind – and that if we are not largely to blame we are certainly guilty of not addressing it. but doing a good job of publicizing that work will also stand you in good stead with the agencies.Why the stem cell sector must engage with social media „„Traffic You can use social media to push and pull audiences to view your site. pride themselves on doing cuttingedge research and publishing it in the toptier journals of their field – then most feel that their part in the conversation is over. makes the case that search engine ranking and online accessibility now far outweigh journal impact factor as a key driver in how many times a paper is cited [1] .com . customers and so on. you can certainly expect your papers and ideas will increasingly be blogged about. investing. increased viewers translate into more chances for collaboration. Increased positive profile all but assures increased invitations to collaborate and/or more favorable responses from those with whom you ask to collaborate. in-person educational and networking events.com) in CA. His reputation as an academic unafraid to ask the unasked questions and engage in a fair and open discussion with both (or all) sides of an issue has opened up opportunities for him that he believes is undoubtedly benefiting his career. For individual professionals this translates into promotions or job offers. It helps give agencies the political support they need to get additional funding in the future… Obviously the work that you do under a grant is paramount.com. Scientists. citation. this means more and/or better quality invites to speak. She pinpoints the core problem as scientists failing to engage anyone other than their scientific peers in a discussion of what they are passionate about and do. buying or engaging in some other action you solicit. investors. presentations. science is almost entirely a one-way conversation. local. linking. this means finding the right partners. It also means finding quality grad students. as a group.

Network you. Jewell T. As Wilcox summarizes: “The ways in which new media can influence. 10 October 2011. we ask them to spend their time and money supporting science. expert testimony. enhanced influence and a wider network. Learning Influence Using your influence to drive the field forward With a higher profile (wider network and influence) comes personal opportunity and benefit but also broader responsibility. ­ Bishop D. “the general public are our customers. For all kinds of selfish and selfless reasons Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. Bishop’s blog. Scientific American blog.” she continues. consultancies. on AstraZeneca’s US business blog (AZ Health Connections). No writing assistance was utilized in the production of this manuscript. 3 Wilcox C. grants or patents received or pending. AZHealthConnections. and revolutionize research are vast and continue to expand and evolve as quickly as the social media landscape” [7] . regulation and funding. Social media for scientists part 1: it’s our job. “In a way. ƒƒ Ultimately. Social media for scientists part 3: win–win. You will be provided opportunity to leverage your profile to: ƒƒ Answer your profession’s critics. we must engage the world around us. that they need to tell their representatives that science and science funding matter. In order to create the kinds of perceptions and solicit the kinds of actions we want from the world around us. (2012) 7(6 Suppl.Buckler The problem is. Social media for scientists part 2: you do have time. ‘knowledge building’ and ‘networking’. A total of 57% of respondents said social media was ‘essential’. future science group 4 6 122 . Figure 1. Why scientists should publicize their findings – for purely selfish reasons. Scientific American Blog. Survey: how our scientists use social media. Shipman M. Tony Jewell posted the results of a survey they had conducted of their scientists and some of their partners around the world. stock ownership or options. Regen. honoraria. Over 70% said they participated in social media professionally but most do so passively. which has real potential to help people. The world around us is engaging online. these publications aren’t really communicating science to anyone but other scientists [4] . Three main benefits of social media: unparalleled learning. your company/organization and your career will benefit from you engaging there too. ‘very valuable’ or References 1 2 ‘valuable’ to their work. Over 60% of respondents said the primary value was in ‘information/collaboration’. 27 September 2011. This includes employment. but then we say we don’t have time to really interact with them? To walk them through what we do. or royalties. 18 June 2012. 26 August 2012. We want their votes and their tax dollars and for them to take the time to understand the issues scientifically. improve. How to bury your academic writing. Every day. contribute to the progress of the field. Scientific American blog. 29 September 2011. 12 February 2012. Scientific American blog.com. ƒƒ Be a voice for the voiceless. ƒƒ Influence public perception. and get them excited about our research? [5] . Wilcox C. Conclusion In February 2012. We tell them what we do is vital. ‘join discussions’ or ‘generate content’ [6] .) 5 Wilcox C. Over 50% ‘read/watch’ but less than 20% ‘post comments’. why it’s cool. Med. ƒƒ Inf luence policy.

StemCellAssays. „„ What is a scientific social network? 6 thriving and inspiring examples. Cellular Therapy and Transplantation. „„ Small G.futuremedicine. 14 June 2011. 2(7).com „„ Bersenev A. „„ Bersenev A. IPScell. Scientific blogging as a model for professional networking online. „„ The Rules of social media. 12 March 2012.com 123 . Top ten tips for blogging for scientists. Fast company.01 „„ Bersenev A. 8 August 2012.com. 27 June 2011. Bull. 141.Why the stem cell sector must engage with social media 7 Wilcox C. 11 June 2010. Twitter for the apprehensive academic.com 22 October 2008. 4 August 2010. „„ Shipman M. 2 November 2011. Yukiko Yamashita. Scientific blogging as a model for professional networking online. If you’re breathing. Evan Snyder. „„ Buckler L. Cell therapy blog. and Joseph Wu Published in affilication with the International Society for Stem Cell Research (ISSCR) Find protocols online at: currentprotocols. Scientific American blog. Comprendia. Nature 479. 10. 2 August 2012.3205/ctt-2010-en-000084. Biol. Taking responsibility for science communication in a digital age. A gentle introduction to Current Protocols in Stem Cell Biology EDITED BY: Thorsten Schlaeger (Editor in Chief). Roger Patient. StemCellAssays. 22285–22287 (April 2012). Time to Tweet. you’re in PR.com „„ Knoepfer P.com „„ Information Resources „„ Buckler L. Guest editorial: it’s time to e-volve. Don’t feel the pain of ignoring social media? Just wait a minute… CellTherapyBlog.com/stem-cells future science group www. Who’s who in the stem cell blogosophere.

With a focus on innovation.SERVA Collagenase NB GMP and research grades available For gentle and efficient cell isolation from various tissues Liberase MNP-S Sterile-A Quality For Stem Cell and Chondrocyte Isolation í í í A highly purified blend of Collagenase I/II and Thermolysin Isolation of human adult stem cell from adipose and tumors Increase cell yield. please visit custombiotech. Miltenyi Biotec provides products and services to advance biomedical research and cellular therapy.com For more information. we develop solutions for sample preparation. viability.com .roche.com Liberase Enzyme Blends are for further processing only.com Tel: (800) 877-3225 www. and functionality Mammalian Tissue Free (MTF) product Minimal lot-to-lot variability Sterile-A according to European Pharmacopeia Research Grade available cGMP and custom sizes available upon request High-yield isolation of cells with excellent viability GMP grade with certified TSE and validated virus safety í í í í í Reliable lot-to-lot consistency and very low endotoxin levels US distributor for SERVA Collagenase NB: Crescent Chemical Co. miltenyibiotec. 2 Oval Drive.collagenase.000 biomedical research and cellular therapy publications to date. and cell culture. Our outstanding portfolio of tools support the translation of basic research to clinical application every step of the way. All rights reserved.crescentchemical.com/liberasegmp www. cell isolation. Inc. in areas that include immunology. cancer. cell analysis. NY 11749 Email: collagenase@creschem.. Roche Diagnostics Corporation Roche Applied Science Indianapolis. © 2012 Roche Diagnostics. neuroscience. Islandia. LIBERASE is a trademark of Roche. and stem cell biology. molecular analysis. Indiana We share your passion for cells See why Miltenyi Biotec products have appeared in more than 20.


Article type


global updates
USA Kirstin RW Matthews & Maude L Rowland Canada Lisa Willemse, Ubaka Ogbogu, Stacey Johnson & Michael Rudnicki UK Emily Culme-Seymour Sweden Outi Hovatta Brazil Rosalia Mendez-Otero & Antonio Carlos Campos de Carvalho
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Global Update USA
Despite the political nature of stem cell research, this area of science continues to flourish in the USA. In 2011, the NIH funded approximately US$1.2  billion in stem cell research – a steady increase from past years – with US$123 million devoted to human embryonic stem cells [101] . According to the ISI Web of Science, more than 4000 USauthored stem cell publications were produced in 2011, accounting for approximately 38% of the world total. Approximately a quarter of these publications were collaborations with authors from other countries [1]. After a tumultuous 2011 court battle over human embryonic stem cell research, this year US politics focused on the growing issues associated with unproven stem cell treatments. One prominent media topic was US professional athletes, such as Peyton Manning and Terrell Owens, seeking therapies abroad for various injuries [102,103] . In addition, the news outlets began to cover a pending FDA lawsuit against a Colorado company, Regenerative Sciences, Inc., for its use of mesenchymal stem cells to treat musculoskeletal and spinal injuries. The lawsuit will determine whether the FDA can oversee autologous adult stem cell treatments as a medical procedure or drug manufacturing [2] . Significant news coverage also surrounded Texas Governor and presidential candidate Rick Perry, who announced that he received stem cell injections while having back surgery in 2011 [3] . Afterwards the governor asked the Texas Medical Board to review its

StemCells, Inc.
StemCells, Inc was founded with the mission “to realize the full potential of stem cells to transform medicine” with the goal to “discover, develop and commercialize breakthrough therapeutics” [105]. Based in Newark, California outside of San Francisco, the company supports research as well as clinical trials. It is currently sponsoring a Phase I/II trial for chronic spinal cord injury, a Phase I trial for Pelizaeus–Merzbacher Disease, and a Phase I trial for Neuronal Ceroid Lipofuscinosis (Batten Disease). Furthermore, StemCells has 25 publications related to its work dating back nearly 20 years, proving its research and therapies are grounded in solid scientific research.

Innovative ­company

Kirstin RW Matthews* & Maude L Rowland

California Institute for Regenerative ­Medicine

Key institution

The California Institute for Regenerative Medicine (CIRM) was founded in 2004 after California voters approved a US$3 billion proposition to invest in stem cell research in 2003 [106]. Their mission is to “support and advance stem cell research and regenerative medicine.” Each year, CIRM awards grants to universities, institutions and companies for basic and applied research, facilities, training grants, and educational programs. To date, CIRM has awarded 519 awards for a total of US$1.4 billion to 65 institutions. In addition, CIRM has created 25,000 jobs and US$200 million in tax revenue. One of CIRM’s main agendas is to translate stem cell research to the clinic. To this end, it has now begun to invest more of its dollars in research with a therapeutic end goal.

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The New York Stem Cell Foundation

Key institution Innovative company
Aastrom Biosciences
Aastrom Biosciences concentrates on cardiovascular disease using adult stem cells. Founded in 1989, its offices are headquartered in Ann Arbor, Michigan [108] . The company is sponsoring two clinical trials: Phase III (special protocol assessment) for critical limb ischemia and a Phase IIa (FDA orphan designation) for dilated cardiomyopathy. In addition, it has over 20 scientific peer-re viewed publications linking its research to the company’s trials.

A strong supporter of stem cell research is The New York Stem Cell Foundation (NYSCF), which was founded in 2005 by business woman and entrepreneur Susan Solomon using her personal funds [107] . The mission of NYSCF ‘is to accelerate cures for the major diseases of our time through stem cell research.’ To accomplish this, it sponsors research at the foundation’s own laboratory facilities, awards grants to young investigators and funds postdoctoral fellowships. NYSCF also hosts symposia, conferences and workshops throughout the year. Even with its limited annual budget of approximately US$18 million, NYSCF has funded some of the field’s top researchers, including Peter Coffey, Kevin Eggan and Dieter Egli.

NIH Center for R ­ egenerative Medicine
The NIH is the major funder of stem cell research in the USA, giving more than US$1 billion in awards each fiscal year. To demonstrate its commitment to stem cell research and regenerative medicine, it established the Center for Regenerative Medicine (NIH-CRM) in 2011. Led by renowned stem cell researcher Mahendra Rao, the center aims to “provide the infrastructure to support and accelerate the clinical translation of stem cell-based technologies and … develop widely available resources to be used as standards in stem cell research” [109]. NIH-CRM funds intramural stem cell research across all of the institutes at NIH and maintains stocks of iPS cell lines and differentiated cell populations for distribution. In addition, NIH-CRM’s website provides an array of information to researchers from informed consent documents to protocols for differentiation processes.

Maude L Rowland, James A Baker III Institute for Public Policy, Rice University, 6100 Main Street, MS-40, Houston, TX, USA 77005 *Author for correspondence: Kirstin RW Matthews, James A Baker III Institute for Public Policy, Rice University, 6100 Main Street, MS-40, Houston, TX, USA 77005; Tel.: +1 713 348 4784; Fax: +1 713 348 5993; krwm@rice.edu

Key institution

future science group



How is scientific knowledge related to experimental practice? How do (or should) social interactions and values impact scientific knowledge? What counts as scientific knowledge anyway – and on whose authority? [114] . similar to the argument being challenged in the FDA versus Regen. This report highlights three individuals. as well as insights on debates among scientists themselves. Med. PhD in history and philosophy of science from Indiana University. Dieter Egli Senior Research Fellow at The New York Stem Cell Foundation and Adjunct Associate Research Scientists in the Division of Molecular Genetics. The technique inserted adult cell DNA into human oocytes allowing them to give rise to blastocysts and ultimately ESCs. and cell replacement therapies. With hundreds of stem cell researchers in the USA. experimental methods. Columbia University.” [113] . which led to a series of commentaries on the topic. (2012) 7(6 Suppl. included a paper he first authored [6–8] . Todd McDevitt and Melinda Fagan. Research focus: Egli describes his focus as “the generation of therapeutically relevant cells for diabetes” [110] . He utilizes somatic cell nuclear transfer (SCNT) techniques to create donorspecific stem cells to be used to study disease. ƒƒ McDevitt has published over 30 scientific articles and coauthored three book chapters. Regenerative Sciences case. model systems and evidential judgments. Key achievements: Education: PhD in bioengineering at the University of Washington in 2001. Switzerland and postdoctoral training in the laboratory of Kevin Eggan at Harvard University.Matthews & Rowland Ones to watch. models and explanations.. Research focus: the relationship between experimental practice. which have no clinically proven efficacy. emphasizing the i nter re l at ion of c onc ept s .. Key achievements: ƒƒ He published the 2011 report in Nature describing the first modified human SCNT cells [5] .” [111. ƒƒ Over the past 5 years. Petit Faculty Fellow for the Institute for Bioengineering and Bioscience and Director of the Stem Cell Engineering Center at Georgia Institute of Technology. screen for new drugs. from various subdisciplines. Research focus: Engineering stem cells into “effective cellular and molecular therapies for the treatment of degenerative disease and traumatic injuries. ƒƒ Egli’s research involves paying women for their oocytes. the paper also highlights major technical barriers for the technique’s application to human cells [6] . 128 ƒƒ McDevitt was the 2010 recipient of the Young Investigator Award from the Society for Biomaterials [113] . Dr Jones claimed that the stem cell transplants were tissue transplants and. there are many young investigators who are doing groundbreaking work. Key achievements: ence from Stanford University (Irving Weissman lab) in 1998. Fagan argues that philosophy of science can help stem cell researchers communicate the value and importance of their work to a broader audience. policy on autologous stem cell treatments after encouragement by his surgeon. which was described by Nature as an “out of the box” opportunity for students interested in stem cell research [9] . Todd McDevitt Associate Professor.) . Described as the “first – albeit genetically abnormal – human pluripotent stem cells” created through SCNT. Bloomington in 2007. ƒƒ He was co-prinicipal investigator for an NSF Integrated Graduate Education and Research Training grant funding a program in stem cell biomanufacturing. therefore. ƒƒ Fagan’s forthcoming book Philosophy of Stem Cell Biology: Knowledge in Flesh and Blood from Palgrave– Macmillan will examine stem cell biology from a philosophy of science perspective. who have stood out this past year and could potentially be the future leaders in this field: Dieter Egli. the Texas Medical Board ultimately approved regulations stipulating only doctors can perform the procedures and requiring oversight by an institutional review board and compliance with state and federal regulations. ƒƒ His Nature research was named the #1 medical breakthrough of 2011 by TIME magazine as well as landing him on its 2011 list of “People Who Mattered. CellTex actively performs stem cell procedures. In April 2012. Department of Pediatrics.112] . future science group Some stem cell researchers even believe these procedures should be prohibited by the FDA. who co-founded the autologous stem cell therapy company. Melinda Fagan Assistant Professor of Philosophy at Rice University Education: PhD in biological sci- Education: PhD at University of Zu- rich. CellTex [4] . Dr Stanley Jones. outside the reach of the FDA. Fagan has published over 20 articles related to philosophy of science and philosophy of biology.

9 Wadman M. Financial & competing interests disclosure Support for the authors was provided through the State of Qatar Endowment for International Stem Cell Policy.com/time/specials/ packages/article/0. Gore A et al. 40–41 (2011). www. 293–294 (2011). No writing assistance was utilized in the production of this manuscript.tx. 393–396 (2011). Fung H-L. ƒƒ Academics are strong and vocal advocates for blocking unproven and unsafe stem cell treatments from being marketed in the USA. Nature 474(7350).html 112 TIME Person of the year. Moving human SCNT research forward ethically. Acknowledgements The authors would like to acknowledge Rice student George Romar for his help in the preparation of this manuscript. Texas prepares to fight for stem cells: nature news. Daley GQ.state. with the development of the new NIH-CRM and National Center for Advancing Translation Sciences that links academic scientists with industry.gov/ future science group www.edu/~mbf2 www. Cell Stem Cell 9(4). Cell Stem Cell 9(4). http://sports.28804.nih.org/about-us/our-mission 108 Aastrom Biosciences.ca.2101745_ 2102309_2102418. Matthews KRW. mattered. 241–243 (2011). Egli D. 13–14 (2012). Overall.nih. PLoS ONE 6(3). devoting over US$30 billion a year to the NIH. References 1 Luo J. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.sos. http://www. In addition. Flynn JM. Regulating autologous adult stem cells: the FDA steps up. Nature 478(7367).aastrom. Nature 478(7367).org/about-us/nyscf-team/ item/183-dieter-egli-phd-senior-researchfellow 111 TIME Top 10 medical breakthroughs: 1.cirm. people who 6 7 Practice”. Key strengths ƒƒ The US federal government strongly supports biomedical research.00. Impracticality of egg donor recruitment in the absence of compensation. Cyranoski D. http://www. Solbakk JH. 109 NIH-CRM.wp7544 104 Texas Register rule change for “Unlicensed Scientists use cloning to create stem cells. http://www.owlnet.html#320 105 StemCells.com/nfl/blog/ shutdown_corner/post/report-terrellowens-is-in-korea-for-stem-celltreatment?urn=nfl. International Stem Cell Collaboration: how disparate policies between the United States and the United Kingdom impact research. it is unclear if these unproven treatments are actually benefiting patients. stem cell scientists worry that a bad outcome could damage the public’s perception of stem cell therapy in general. Nature 483(7387). http://mcdevitt. 3 ABC news-medical unit.2101344_21007 69_2100763.com 129 . Inc. e17684 (2011).gov 102 “Peyton Manning’s Stem Cell Hail Mary”. Ecklund EH. But both the companies and patients have been averse to letting the FDA regulate or evaluate the procedures despite the fact that most scientists and ethicists have been supportive. 377–378 (2011).us/texreg/archive/ March92012/PROPOSED/22.00.com „„Websites 101 National Institutes of Health. 295–297 (2011). Biomedical research: growing with the flow.time. Yahoo! sports. 107 NYSCF.com 106 CIRM. scientists have been divided on whether the Texas Medical Board decision benefitted or hurt regulation of unproven ­treatments [104] . Noggle S.edu/ 114 Melinda Bonner Fagan. 70–75 (2011). 8 http://www. Cell Stem Cell 9(5).com/blogs/ health/2011/09/19/peyton-manningsstem-cell-hail-mary/ 103 “Report: Terrell Owens is in Korea for stem http://nyscf. Cyranoski D. Human oocytes reprogram somatic cells to a pluripotent state. Campbell AV. Hyun I.gatech.yahoo. EXAMINING%20BOARDS.rice. Lysaght T. Several companies have been misleading in the efficacy and applicability of the therapies. with over US$1 billion dedicated to stem cell research.html 113 Todd McDevitt. http://www.com/time/specials/ packages/article/ 0. Furthermore. ƒƒ NIH strongly encourages stem cell research and translational medicine.go. http://www.stemcellsinc. 4 5 cell treatment”.28804.time. 2 http://crm. http://abcnews. http://www. Chen AE.futuremedicine. Stem cells: triple genomes go far. Nature 477(7365).nyscf.USA It remains to be seen if this policy is more or less stringent than current federal regulations. Stem-cell therapy takes off in Texas. Saphier G et al. Solnick RE.gov 110 Dieter Egli.



Key institution Terry Fox Research Institute Terry Fox Research Institute involves collaboration between cancer hospitals and research organizations across Canada. Canada. 132–135 ISSN 1746-0751 . Canada Michael Rudnicki. An example of this collaboration is in the recent formation of the Till and McCulloch Meetings. University of Toronto The Institute of Biomaterials & Biomedical Engineering. Québec in May 2012. One of the greatest strengths of the research conducted in Canada is its ability to break disciplinary boundaries and thus produce findings of incredible depth and breadth. University of Alberta.AROUND THE WORLD Global Update Canada Lisa Willemse*. Ontario and Québec. Toronto. Canada Stacey Johnson. provincial: Ontario Stem Cell Initiative and Québec’s ThéCell) for the largest scientific conference the 132 Key institution Institute of Biomaterials & Biomedical Engineering. despite obvious geographical challenges. Centre for Commercialization of Regenerative Medicine. and engineering in a clinical setting. Ontario. research results and innovative programs to leverage investments in the sector. this event brought together several stem cell and regenerative medicine organizations from various regions across the country (pan-Canadian: SCN and Centre for Commercialization of Regenerative Medicine. Ottawa. Research falls into the fields of neural and sensory systems. Stacey Johnson & Michael Rudnicki If Canadians have a global reputation for being ‘nice’. Med. primarily in British Columbia. Ontario. Canada continues to see significant achievements and changes that will have a broad impact on the ability to move translational research forward in the near future. nanotechnology and systems biology.2217/RME. lwillemse@stemcellnetwork.66 © 2012 Future Medicine Ltd Regen. Ontario. Ottawa. engineering.). Canada’s Stem Cell Network (SCN). medicine. Ubaka Ogbogu. which were held in Montréal. Alberta. has played a catalytic role in supporting crossdisciplinary research and in ensuring that a collaborative. located in the heart of Toronto’s Discovery District. Edmonton. Stem Cell Network. Levering the success of earlier SCN scientific conferences.12.ca 10. The Canadian stem cell and regenerative medicine field is particularly strong in terms of collaboration. It currently supports translational programs with a focus on tumour site-specific research and cancer biomarkers. a federally funded Centre of Excellence since 2001. Stem Cell Network. networked community exists in Canada. Alberta. is a multidisciplinary organization with a bioengineering focus that draws scientists and practitioners from applied science. Ubaka Ogbogu. biomaterials. then our propensity for scientists to collaborate should come as no surprise. Canada *Author for correspondence: Lisa Willemse. (2012) 7(6 Suppl. tissue engineering and regenerative medicine. dentistry and the life sciences.

com 133 .Canada Northern Therapeutics Northern Therapeutics is a biopharmaceutical company committed to the discovery and development of novel cell and gene therapies to extend and enhance the quality of the lives of people suffering from chronic life-threatening pulmonary disorders. cell expansion. cell collection. in the absence of toxicity and major side effects. and final implant formation. University of Montréal The Institute for Research in Immunology and Cancer was one of the first research centers in Canada to adopt integrated systems biology as the core of its research model. interlinked bio­ reactors that provide precise control over the steps of cell source isolation. with a particular ­ focus on clinical translation. Ontario. Québec and Ottawa. proteomics and bioinformatics to inform research in cancer. future science group www. Innovative company Key institution Institute for Research in Immunology and Cancer. for example. Its 400 members use genomics. Northern Therapeutics has offices in Montréal.  The company has developed a novel method for selective gene transfer and regenerative cell therapy targeting the pulmonary vasculature with the hope of repairing damaged lung tissues in a number of respiratory and cardiopulmonary conditions. Ontario. Octane’s vision is to deliver cell therapy and tissueengineered implants through turnkey automated processes. Canada. cell washing.futuremedicine. Canada. Octane Biotech Innovative ­company Octane Biotech focuses on clinical systems for cell and tissue therapy. Octane is based in Kingston.

a not-for-profit network that supports the development of technologies that accelerate the commercialization of stem cells and biomaterials-based technologies and therapies. Formed in 2010. Ontario. with the announcement of Dr Alan Bernstein as its Board Chair. Cell Stem Cell 11(1). Meanwhile. Riedel MJ et al. 23–35 (2012). SCN will also announce new projects that will build on a growing cell therapy platform and bring together cGMP facilities from across the country in order to streamline efforts nationally. Her laboratory hopes that the lessons learned from studying neural development can be used to understand and potentially repair nervous system diseases and injury. The federal government recently passed legislation that included amendments to the Assisted Human Reproduction Act. Research focus: understanding how Recent paper of note: Rezania A. Owing to its success.. The RMC. Aaron Schimmer University Health Network. Following this. Med. there are many young investigators who are doing groundbreaking work. policy changes were once again at the forefront of news in Canada. Maturation of human embryonic stem cellderived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Other Ones to watch. Toronto. became one of an elite group of international regenerative medicine translation centers to join the Regenerative Medicine Coalition (RMC). ­ ological studies of Type 1 and Type 2 diabetes. launched in May 2012. the SCN-secured its final tranche of funding. Devito LM et al. is expected to become a major player in the upcoming years. growth. SCN announced investment in three global projects that are aimed at leveraging research in which Canada has substantial strength and capacity: drug discovery using cancer stem cells. Ogbogu. (2012) 7(6 Suppl. Ontario. which aims to serve as a champion for stem cell research in Canada. His team is also devising methods to encapsulate b-cells to protect them from immune rejection. It also abolished Assisted Human Reproduction Canada. planning for the 2013 Meetings are already underway. Screening of chemical and siRNA libraries to better understand biological pathways. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. This was the first major event for the recently formed Foundation.) future science group . The amendments implemented a 2010 Supreme Court of Canada ruling that invalidated several provisions of the law on the basis that the power to enact those provisions belonged to the provinces. With hundreds of stem cell researchers in the Canada. ­Vancouver. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. from various subdisciplines. Jhas B et al. This report highlights three individuals. Cancer Cell 20(5). the Centre for Commercialization of Regenerative Medicine. which governs embryo research. Canada Freda Miller Hospital for Sick Children. and. Johnson & Rudnicki country has yet to see. Alberta. In January 2013. Toronto. growth factors in the neural environment regulate the genesis of neural cell types from embryonic neural stem cells and determine neuronal survival. molecular therapeutics to modify cells in vitro to produce insulin or to expand pancreatic islet cells for transplantation. including many aspects of stem cell research. 134 Regen.Willemse. The RMC is being led by Frank-Roman Lauter of the Berlin–Brandenburg Center for Regenerative Therapies. In a year of celebration marking the 50th anniversary of the identification of stem cells by James Till and Ernest McCulloch. apoptosis and the pathogenesis of leukemia. 674–688 (2011). who have stood out this past year and could potentially be the future leaders in this field. and ultimately connectivity. neural and tissue repair using endogenous stem cells. Sris- kanthadevan S. The aim of the RMC is to harness expertise to advance the field of regenerative medicine and to commercialize new discoveries. Research focus: chemical biology Recent paper of note: Wang J. and expansion of hematopoietic stem cells for clinical use. valued at close to CAN$20 million. and to identify molecules that may serve as leads and prototypes for novel therapeutic agents for the treatment of leukemia and other malignancies. 2016–2029 (2012). Research focus: Cellular and physi- and drug discovery with a focus on the apoptosis pathway. Finally. Germany. based out of Berlin. the federal agency charged with the responsibility of enforcing the legislation. the Canadian Stem Cell Foundation recognized the achievement with a formal gala in Toronto. British Columbia. in 2011. Ontario.. Bruin JE. to be held 22–25 October in the mountain town of Banff. Gallagher D. Diabetes 61(8). Canada Timothy Kieffer University of British Columbia. Canada Recent paper of note: Skrtic M.

Inc. such as the creation of human embryos for research purposes. remain in force. recognized world leader in hematopoietic and cancer stem cells ƒƒ Public healthcare system well suited to clinical trials. future science group www. ƒƒ Strong public support for stem cell research. as well as our business principles.com StemCells. An unwavering commitment to rigorous science characterizes our culture. Overall. Key strengths ƒƒ Highly collaborative culture across all research disciplines. Credited with an impressive record of discoveries and firsts. targeting central nervous system (CNS) disorders with our HuCNS-SC® product candidate. targeting liver disease with our proprietary hLEC™ human liver engrafting cells. is the first and only company to complete two US clinical trials using human neural stem cells. guiding our scientific and clinical integrity. the StemCells. expert testimony. StemCells.Canada changes include repeal of the licensing regime for research activities permitted by the legislation. ƒƒ 50 years of experience in the field.futuremedicine. grants or patents received or pending. or royalties. Our liver program is also among the first of its kind. the legislative changes will reduce regulatory overlaps and serve to improve the oversight of stem cell research in Canada. stock ownership or options. aspects of the law that criminalize certain research activities. Inc. honoraria. This includes employment. However. NASDAQ: STEM www. Inc. team has a distinguished heritage of scientific achievement in stem cell biology. develop and commercialize breakthrough therapeutics and enabling tools and technologies for research and drug discovery. is applying its scientific and industry leadership in stem cell biology to discover. No writing assistance was utilized in the ­ production of this manuscript. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. consultancies.com 135 1 .stemcellsinc.

a single-center Phase I/II study currently being performed in Pittsburgh. which all act to further encourage a pan-UK collaborative environment. (2012) 7(6 Suppl. Azellon Cell Therapeutics Innovative company Azellon is focused on developing stem cell therapies for the repair of avascular meniscal tears. The technology behind Azellon was developed by cofounder Professor Anthony Hollander over the last 9 years and is based around an autologous stem cell-populated construct for implanting onto the site of a meniscal tear. based in the Core Technology Facility in the University of Manchester Innovation Centre. clinical. PA. one. as well as linking up to other centers in the UK through a strong collaborative network. with the continued enrolment of patients onto two pioneering Phase I clinical trials: ReNeuron’s ReN001 stem cell therapy for stroke (PISCES) in Southern General Hospital. who brings his wealth of manufacturing know-how to direct world-class research and lead on a number of high-value projects. as well as for scar contractures. thus leading to strong. industry and government. Med. The funding landscape for the sector has evolved from previous years to more fully embrace development and translation. Key ­institution Loughborough University Founded in 1996. long-term repair. the UK cell therapy community continues to thrive and impact heavily upon the worldwide sector. The center is led by Professor David Williams. Overall.2217/RME. ICX-RHY is a suspension of human dermal fibroblasts in cell storage medium ready for injection into the skin. USA. with an established research base. Intercytex Innovative ­company Intercytex is a cell therapy product and services company re-launched in November 2010. A membrane containing adult stem cells harvested from the patient’s iliac crest is surgically inserted into the tear in the meniscus and. and the other. the focus has now moved to encompass far more post-research activities. once in place. Loughborough University has rapidly grown into one of the UK’s top universities. a Phase II trial taking place in London using ICX-RHY to treat skin erosions in patients suffering from epidermolysis bullosa.AROUND THE WORLD Global Update UK Emily J Culme-Seymour* 2012 has been an exciting year in the UK with substantial development on every front – research. The Engineering and Physical Sciences Research Council Centre for Innovative Manufacturing in Regenerative Medicine was established at Loughborough in 2010 and is focused on translating ideas into treatments through pinpointing commercially robust practices and processes that can improve product development and manufacturing processes. The company is currently involved in two clinical trials in the UK and the USA.12. looking at the safety and efficacy of ICX-RHY to increase the joint mobility in patients suffering from dermal scar contractures. appropriately named a ‘cell bandage’. a solid approach to translation and a small but growing commercial sector that is going from strength to strength. The technology has already been proven highly efficacious in an in vitro model and following the successful completion of a £0. it is now being taken into the clinic following regulatory go-ahead on a ten-patient Phase I/IIa trial. including the severe genetic skin disorder epidermolysis bullosa. 136 10. the newly implanted cells migrate between the implant and the original tissue. UK.65 million financing round in November 2011. 136–138 ISSN 1746-0751 . scheduled to begin in late 2012 at Southmead Hospital.73 © 2012 Future Medicine Ltd Regen. as well as ongoing developments with the Cell Therapy Catapult. The main focus of the company is developing their lead product ICX-RHY (VAVELTA®) to treat a variety of skin-related problems.). Bristol. Greater Glasgow and Advanced Cell Technology’s retinal pigment epithelial cells derived from human embryonic stem cells for Stargardts macular dystrophy and dry age-related macular degeneration at Moorfields Eye Hospital. London. including the provision of £180 million available for biomedical research via the Biomedical Catalyst Fund (joint Technology Strategy Board and Medical Research Council [MRC] funding) and a further £25 million through the UK Research Council’s UK Regenerative Medicine Platform initiative. In particular. including world-leading cell therapy manufacturing activities.

the Medical Research Council. gene therapy and cell therapy research and development.futuremedicine. the Biotechnology and Biological Sciences Research Council and the Royal Society of Medicine together with twenty leading research universities. including Cambridge.UK UK Stem Cell Foundation The UK Stem Cell Foundation was founded in 2005 with the aim of accelerating stem cell translation from the laboratory bench to routine clinical practice. The UK Stem Cell Foundation is actively targeting the gap between discovery research and latestage clinical trials by funding and leveraging resources to support flagship UK projects. as well as at the Royal Free Hospital and Great Ormond Street Hospital. Imperial College. brings together 186 research groups from seven faculties. Edinburgh. The UCL Cancer Institute. In addition.com 137 . and UCL is leading on translating discoveries into patient-ready therapies for the clinic within other departments. Department of Hematology and the Advanced Centre for Biochemical Engineering are among the many UCL departments that are spearheading cutting edge stem cell. manufactures and commercializes patient-specific cellular immunotherapy products comprised of antigen-specific T cells. has dedicated over £7. The company is currently sponsoring two late-stage trials addressing the use of adoptive cellular therapy in treating cytomegalovirus infections. with the ultimate goal of achievement of new knowledge that has direct economic benefit to the UK. and plans a third study treating advenovirus infections. Cell Medica are developing a cell therapy using immune cells to recognize and kill malignant cells expressing Epstein–Barr virus antigens. The UCL Centre for Stem Cells and Regenerative Medicine. future science group www. USA). Institute of Neurology. The Foundation funds promising clinical projects in UK universities and hospitals and. several specialized hospitals and a number of institutes. The Foundation has received endorsements from Government. and it is probably now the global leader in clinical cell and gene therapy applications. such as the Institute of Ophthalmology and the Ear Institute. and has developed cell therapies for certain viral infections that follow a bone marrow transplant. all located in London. demonstrates world-class ability in the field of stem cell research. Key institution University College London As one of the world’s top five universities and with grand challenge themes in both human wellbeing and global health. The company was founded in 2006 by the current CEO. it is unsurprising that University College London (UCL). officially launched over 3 years ago.5 million to the sector. in collaboration with the Center for Cell and Gene Therapy at Baylor College of Medicine (TX. Gregg Sando. Manchester and University College London. Key institution Innovative company Cell Medica Cell Medica develops. to date.

as part of King’s Health Partners. and investigating viral (papillo­ matosis) and bacterial infections of the throat. (2012) 7(6 Suppl. is identifying molecules and signaling pathways that can be used to enhance repair in the damaged CNS in multiple sclerosis. translation and high value manufacturing of advanced therapies. Imperial College London. UK 138 Regen. repairing paralysed laryngeal nerves. education and training. tissueengineered organ transplant in 2008 and has completed a number of airway replacements and laryngeal transplantations since. Research focus: at the forefront of research into the use of stem cells in regenerative medicine and disease.) future science group . Med. ƒƒ Significant funding streams open to the cell and gene therapy sectors from multiple organisations. Financial & competing interests disclosure EJ Culme-Seymour is an investigator on the British Regen Industry Tool Set (BRITS) project funded by the Technology Strategy Board under their Regenerative Medicine Program: Value Systems and Business Modelling. Research focus: focuses on understanding the impact of the bone marrow in inflammatory diseases and elucidating the molecular mechanisms regulating the exit of leukocytes and stem cells from the bone marrow. including a network of five Academic Health Science Centers located across the UK that ensure partnerships between universities and healthcare providers. Sara’s research output is being used to develop therapeutics that stimulate the activity of endogenous stem cells to promote tissue regeneration. with new state-of-the-art facilities and a world-class team of scientists and clinicians. including commitment to research. Fiona Watt Professor and Director of the Centre for Stem Cells & Regenerative Medicine at King’s College London (KCL). inputs into government policy and represents the wider industry community to key stakeholders located in the UK and globally. Wellcome plus many other charities. clinical services. No writing assistance was utilized in the production of this manuscript. Fiona moved from the position of Deputy Director of the Cambridge Cancer Research-UK Institute at the University of Cambridge to found the new center at KCL in 2012.Culme-Seymour Ones to watch. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. ƒƒ Highly collaborative environment across the UK that transcends the traditionally perceived barriers between academia. which focus on research. Charles ffrench-Constant Director of the Medical Research Council Centre for Regenerative Medicine and Chair of Medical Neurology at the University of Edinburgh.. ƒƒ Increasing focus on achieving clinical translation. clinical medicine and industry. Medical Research Council. 14a Clerkenwell Green. Research focus: the principal focus Research focus: led the European team that successfully performed the world’s first stem-cell based. London EC1R 0DP. Martin Birchall Chair of Larynogology at The Ear Institute within the Faculty of Brain Sciences. Key strengths ƒƒ Robust UK government support and interaction. London Regenerative Medicine Network. Sara is also involved in a variety of public engagement and outreach activities. with a particular interest in the development and renewal of skin stem cells. including the understanding of laryngeal immunity to help people with inflammatory (laryn­ gitis) and malignant (throat cancer) conditions. The Centre is planning to bring together the cutting-edge stem cell research currently taking place across KCL and its partner NHS trusts. The MRC Centre is based at the Scottish Centre for Regenerative Medicine Building. Martin has also assembled bespoke teams to address a variety of throat disorders. including Technology Strategy Board. ­ *Author for correspondence: Emily J Culme-Seymour. Sara Rankin Professor of Leukocyte and Stem Cell Biology and Head of Regenerative Pharmacology group at the National Heart and Lung Institute.. other ongoing collaborative projects in Charles’ laboratory address spinalcord injury and schizophrenia. Additionally. ƒƒ A united industry voice through the BioIndustry Association Cell and Gene Therapy Industry Group which participates fully in UK and EU lobbying activities. University College London.

© 2012 EMD Millipore Corporation. Darmstadt.emdmillipore. Germany. Stem cells are a new frontier that hold great potential. Darmstadt. Billerica. MA USA. Our Mobius® CellReady 3 L bioreactor is a convenient and cost-effective tool for the culture of clinical grade human mesenchymal stem cells (hMSCs). Darmstadt. Mobius is a registered trademark of Merck KGaA. efficiency and cost effectiveness. One giant leap for science. It is ready to use out of the box complete with protocols for transferring and optimizing your stem cell culture in a bioreactor format. reproducibility. Germany EMD Millipore and the M logo are trademarks of Merck KGaA. Germany. All rights reserved.One small cell from man. But leaping from research to production presents a new set of challenges: consistency. Get out of this world results with the Mobius® CellReady 3 L bioreactor.com/stemcells EMD Millipore is a division of Merck KGaA. . please visit www. For more information on our stem cell program and the Mobius® CellReady 3 L bioreactor.

ƒƒ Established stem cell research networks with international connections. are the main commercial products of this company. Many groups have been active partners in projects funded by the European Commission.12. is a premier provider of stem cell-derived products and technologies. human embryonic stem cells. Optimizing the stem cell type for these constructs is ongoing. The Swedish Research Council and other funding organizations have been very positive for stem cell research. a Business Unit of Cellectis Group (Alternext: ALCLS). Med. has been acting in the stem cell area already for several years. It has now also widened its development and production to new defined stem cell culture and cryopreservation media. Innovative company Human embryonic stem cell lines Human embryonic stem cell lines have been derived since 2002 by developing the quality of the cells to clinical grade. human-induced pluripotent stem cell-HEPTM. induced pluripotent stem cells and human mesenchymal stem cells. coordinated by Professor Katarina LeBlanc. Cellectis stem cells. Pharmacologic testing kits using cardiomyocytes. Key strengths ƒƒ Permissive culture and society with clear.74 © 2012 Future Medicine Ltd Regen. They have pioneered areas such as clinical treatment of Parkinson’s disease.2217/RME. hepatocytes and neural cells differentiated from pluripotent stem cells. being one of the world leaders in this. Professors Karl Tryggvason and Outi Hovatta’s collaboration resulted in animal substance-free. Human mesenchymal stem cells Human mesenchymal stem cells have been for the first time used very successfully in treatment of severe graftversus-host reaction [3] and these clinical studies continue at an international level. feeder cellfree chemically defined conditions to establish clinical-grade human embryonic stem cell lines [2] . more recently particularly in hepatocyte and cardiomyocyte differentiation [5]. In 2011. Cellartis Cellartis in Gothenburg. recently fused with Cellectis [102] . Successful transplantations of trachea using a tissue-engineered product with cells cultured into a scaffold have been made recently [1]. Vitrolife Innovative ­company Vitrolife [101] in Gothenburg is an established manufacturer of culture media and other products for in  vitro fertilization. 140 10. The company is carrying out high-quality research and development work. and there is a favorable law in Sweden regulating human embryonic stem cell research. ƒƒ Relatively good research and development funding. (2012) 7(6 Suppl. 140–142 ISSN 1746-0751 . More than 50 hESC lines have been derived while revealing the signaling mechanisms regulating their pluripotency and growth. ƒƒ Long tradition with Biotech companies. nonrestrictive legislation of stem cell research. It has recently launched a human-induced pluripotent stem cell-derived hepatocyte product.). Clinical trials are ongoing with mesenchymal stem cells in graft versus host disease and osteogenesis imperfecta.AROUND THE WORLD Global Update Sweden Outi Hovatta* Swedish researchers have been very active in the stem cell field for many years. combined with culture medium and culture systems. developmental biology including early stem cells.

Tel. ­ fibroblasts for ­example. feeder-free system for derivation of human embryonic stem cell lines from single biopsied blastomeres of human embryos. a strong focus [4.7]. There are many other outstanding neuroscientists based at the Karolinska Institutet. It also produces kit of chemically defined matrices and chemically defined culture media for clinical-grade cells.futuremedicine. with treatment of neurodegenerative disorders. Different aspects of neural stem cells. Karolinska Institutet. outi. Key institution *Author for correspondence: Outi Hovatta. from development to therapies have been studied at high impact level. comparable to other cell types. Karolinska University Hospital Huddinge.com 141 .: + 46 8585 83858. Biolamina’s products have made cultures of human pluripotent stem cells very simple. The company manufactures all human laminins in human cells cultures.Sweden Innovative company Biolamina Biolamina [103] in Stockholm has successfully made excellent matrices for different types of stem cells. SE 141 86 Stockholm. future science group www. including a fully xeno-free. and it has a GMP-grade production facility for clinical-grade cells.hovatta@ki. Sweden. K57. Endodermal lineages and possible stem cell therapy for diabetes have also been active research topics in Lund [8]. Professor Jonas Frisen’s group has been productive in identifying mechanism of how the adult brain repairs itself [6] . Key institution Karolinska Institutet Karolinska Institutet is a university that has wide stem cell research activities within collaborating centers.se The University of Lund The University of Lund has an outstanding Stem Cell Center. particularly Parkinson’s disease and stroke.

Research focus: her topic. Why is it taking so long to develop clinically competitive stem cell therapies for CNS disorders? Cell Stem Cell 10(6).) future science group .. Med. Self-renewal of human embryonic stem cells on human recombinant laminin-511 in chemically defined xeno-free medium and environment.Hovatta Ones to watch. Developmental Neurobiology at Lund University. 45–56 (2010). 8 5 Ameri J. their progenitor cells and lipid stores in lean and obese individuals. 110–113 (2011). Lancet 378(9808). 3 7 www. Stem Cells 28(1). Assistant Professor in Karolinska Institute. 349–350 (2012).biolamina. There are so many promising young stem cell scientists is Sweden. Her primary interest is in investigating the origin and turnover of adipocytes. Malin Parmar PhD. Kirsty Spalding has been recently studying lipid turn­ over and cell age are studied using radiocarbon dating. obesity. Dynamics of human adipose lipid turnover in health and metabolic disease. expert testimony. Rodin S. from Jonas Frisen’s team. Lindvall O. now independent. consultancies. Baiguera S et al.cellectis. Concise review: human pluripotent stem cell-based models for cardiac and hepatic toxicity assessment. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. 6 www. Alici E.vitrolife. No writing assistance was utilized in the ­ production of this manuscript.com 103 Biolamina. Kirsty Spalding. Associate Professor at Wallenberg Neuroscience Center. Cell Reports 1(6). Ståhlberg A. Chien K et al. This includes employment. that it almost impossible to name just a few of them. FGF2 specifies hESC-derived definitive endoderm into foregut/midgut cell lineages in a concentration-dependent manner. Transplantation 81(10). 660–662 (2012). Sartipy P. Wolf DA et al. Rasmusson I et al. Bernard S. Göritz C. stock ownership or options. Björklund A. 657–659 (2012). grants or patents received or pending. Together these diseases form a cluster referred to as the metabolic syndrome. Kirsty Spalding PhD.com 102 Cellectis. 1997–2004 (2011). after a most productive postdoc period in professor Jonas Frisen’s group. 4 Parmar M. 703–714 (2012). Cell Stem Cell 10(4). Domogatskaya A. Selected publication: Kirkeby A. Therefore. Cell Stem Cell 10(6). Salehpour M et al . Björquist P. Such cells can probably be used for clinical treatment in the future. References 1 Jungebluth P. By studying cell turnover in a variety of different adipose depots (such as various subcutaneous adipose depots as well as visceral depots) we aim to better understand the regulation of the fat mass in humans. Selected publication: Arner P. Grealish S. with generation of chemically defined methods for differentiating dopamine neurons. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Uzunel M. Understanding the dynamics of adipocyte turnover may shed new light on potential treatments for ­obesity. Sweden genitors and functional neurons from human embryonic stem cells under defined conditions. Generation of regionally specified neural pro- Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.. Sweden Research focus: Malin Parmar has been focusing on the development of neurons from human embryonic and induced pluripotent stem cells. Frisén J. 2 „„Websites 101 Vitrolife. Nat. Generation of transplantable striatal projection neurons from human ESCs. Biotechnol. 611–615 (2010).com 142 Regen. 744–748 (2011). honoraria. (2012) 7(6 Suppl. Ringden O. Stem Cells 29(5). 28(6). Nature 478(7367). is another Swedish scientist excelling in the field of stem cell research. Pedersen J et al . Neural stem cells and neurogenesis in the adult. She has received a highly competed European Research Council (ERC) grant in 2012. constitutes a public health problem by enhancing the risk for diseases such as diabetes. www. Dr Malin Parmar from Lund University is a very promising scientist developing cell therapy for Parkinson’s disease [4]. fatty liver disease and atherosclerosis. 1390–1397 (2006). or royalties.

StemCellsTM. Sign up for your free individual subscription at www.com.StemCellsTM.subscribe.Bridging Stem Cell Research and Clinical Trials Video Interview Series Coming Soon Stem Cells Translational Medicine is an internationally peer-reviewed journal dedicated to advancing the clinical utilization of stem cell molecular and cellular biology closer to accepted best practices. offering the distinct possibility of eventually repairing or replacing tissues damaged from disease. Find high-impact articles that focus on: • Compelling cell implantation technologies • Novel tissue/organ repair and regeneration protocols • Proof-of-concept studies in degenerative disease models • Data from negative clinical trials The potential of stem cells therapies and regenerative medicine is both provocative and powerful.StemCellsTM. www.com www. including certain cancers.com .

bone marrow. Instituto de Biofisica Carlos Chagas Filho.ufrj. Analysis of scientific activity in the field shows that publications from Brazilian scientists have increased steadily from nine publications in 2000 to 152 in 2011. only research with adult stem cells was supported by federal funding. The group coordinated by Dr Lygia da Veiga Pereira was responsible for the establishment of the Brazilian human embryonic cell lines (from blastocyst donated by Brazilians). since the great majority of the publications coming out of Brazil are authored only by Brazilian scientists. neonatal tissues). this growth still puts Brazil in a modest 19th place in comparison to other countries in stem cell research. Even with the ban on hESC research until 2008 the country made significant advances in stem cell research in the last decade [1]. rmotero@biof. cardiac and neural stem cells. Investments since 2005 have mounted to over US$50 million. 144–147 ISSN 1746-0751 . The university houses several groups under the leadership of professors or young investigators. adipose tissue. mesenchymal stem cells of diverse origins (e.g. In Excellion & CellPraxys Two companies are offering cell therapy services in Rio de Janeiro – Excellion offers cultured fibroblasts for rejuvenation and CellPraxys offers chondrocytes for cartilage lesions. preclinical (33 projects) and clinical research (four  projects). CIRM and the Brazilian Network for Cell Therapy (RNTC) [101] will hold a workshop involving 30  scientists from Brazil. This network (RNTC) involves eight Cell Technology Centers (CTCs) and 52  research laboratories financed through Requests for Application sponsored by the Ministry of Health and the Ministry of Science and Technology. Brazil. International cooperation also needs to be improved.: +55 212 562 6554. Achievements in the field were supported by policies directed to provide federal funding for stem cell research by the Ministry of Health. but contemplate most physiologic systems. financing 110 projects. The 52 laboratories that are supported by the Request for Application are conducting basic (15 projects). Professor of Physiology and Biophysics. Innovative companies Key institution Universidade de Sao Paulo This is the largest state university in the country and together with The Federal University of Rio de Janeiro is responsible for most of the research in stem cells. Argentina and California (USA) to ­d iscuss ­possible collaborations.. acarlos@biof. the first Brazilian hESC line was derived. It is hoped that a recent binational program sponsored by the Argentinian and Brazilian governments may lead to more international collaboration.2217/RME. Right after legislation permitted.AROUND THE WORLD Global update Brazil Rosalia Mendez-Otero* & Antonio Carlos Campos de Carvalho Research using human embryonic stem cells (hESCs) was debated for 4 years in the Brazilian Supreme Court before being legally approved in 2008. In October. Universidade Federal do Rio de Janeiro.br *Author for correspondence: Rosalia Mendez-Otero. These projects concentrate on the nervous and cardiovascular systems. Tel. (2012) 7(6 Suppl. Med. CellPraxys is attempting to license a product for therapy of refractory angina. Distributed throughout the country the CTCs are working to produce human embryonic and induced pluripotent stem cells. The eight CTCs have the mission of producing clinical-grade stem cells (manufactured under c-GMP conditions) to be used in current and future clinical trials. ranging from basic to clinical research. Before that. Universidade Federal do Rio de Janeiro.ufrj.84 © 2012 Future Medicine Ltd Regen. Brazil. Another important initiative was the signing of a Memorandum of Understanding between the Brazilian National Research Council (CNPq) and the California Institute for Regenerative Medicine (CIRM) in 2012. still in 2008 [2]. Antonio Carlos Campos de Carvalho. Brazil has achieved international recognition by the clinical trials performed in the country using cell therapies.12. Instituto de Biofisica Carlos Chagas Filho.). Although extremely significant.br 144 10. Professor of Physiology and Biophysics.

This was the largest study in the country in stem cell therapy. One of the interesting aspects of this institution is the close interaction among the groups working in the basic science departments and the clinical departments at the University Hospital. Under the leadership of Dr Paulo Brofman. Many of these studies were multicenter studies conducted in several hospitals. in cirrhosis and more recently in spinal cord injury. the group has played an important role in preclinical and clinical studies in heart diseases. a cardiac surgeon. Fundação Fiocruz is a research institution of the Ministry of Health while the Hospital São Rafael is a nonprofit organization.Brazil Key institution Fiocruz and Hospital Sao Rafael The Fundação Fiocruz and the Hospital São Rafael in Bahia. Brazil (in the northeast) are Institutions that have contributed importantly to the development of research groups in stem cells in the northeast part of the country.futuremedicine. Several Phase I clinical studies using adult stem cells were concluded or were coordinated by the research groups at this university [13]. Brazil) is the largest public federal university in the country and houses several research groups that are involved with stem cell research. The Bahia institutions have pioneered both animal studies and clinical trials in Chagas disease. Universidade Federal do Rio de Janeiro The Universidade Federal do Rio de Janeiro (Rio de Janeiro. The research areas range from human embryonic stem cells and human induced pluripotent stem cells to preclinical studies and clinical trials with adult stem cells. Key institution future science group www.com 145 . notably for cardiac ischemic diseases. an institution of the Ministry of Health located in Rio de Janeiro which coordinated the Phase II/III study in cardiac diseases [14]. such as the Instituto Nacional the Cardiologia. Key institution Pontificia Universidade Católica do Parana The Pontificia Universidade Católica do Parana is lo cated in the south region of Brazil and has contributed importantly to the development of stem cell therapies in Brazil.

despite efforts by the Federal Government to change this picture in recent 146 decades. PhD at the Mount Sinai Graduate School – 1994. there are many young investigators who are doing groundbreaking work. Education: Physics at the Catholic University in Rio de Janeiro. Key achievements: and induced pluripotent stem cells Key achievements: patients Key achievements: ƒƒ Derived the first Brazilian human embryonic stem cell line in 2008 ƒƒ Participated in the International Stem Cell Initiative ƒƒ Proposes to establish an induced pluripotent stem cell ba nk representing the Brazilian ethnic population ƒƒ Derived induced pluripotent stem cell from schizopshrenic patients ƒƒ Generated a defined media for pluripotent cell culturing ƒƒ Maintains a blog and a highly visited page for public information about stem cells ƒƒ Coordinated the safety study using bone marrow-derived stem cells in stroke patients ƒƒ Coordinates the efficacy study in stroke patients planned to start this year auto­ immune diseases. preclinical aspects of stem cell research in the country. who have stood out this past year and could potentially be the future leaders in this field. ƒƒ Highly motivated and dedicated students – from undergraduate all the way to post-doctoral fellows – interested in stem cells and cell therapies.) future science group . Med. most of the knowledge produced in Brazil in the stem cell and cell therapy field is generated in two public universities of Rio and São Paulo. the recent publication of an efficacy trial using bone marrow-derived cells in the setting of Chagasic cardiomyopathy [8] . Stem cell research follows the pattern but there are exceptions. Regen. Last. have also been promi- Key strengths ƒƒ Continued support by the Ministry of Health. The Federal Uni- versity of Rio de Janeiro (Universidade Federal do Rio de Janeiro) and the State University of São Paulo (Universidade de São Paulo) concentrate the largest number of research groups working in basic. PhD at the Universidade Federal do Rio de Janeiro (2004). Of note.. Research focus: embryonic stem cells Education: Biology at the Federal University of Rio de Janeiro. However. The cardiovascular area has also seen major contributions from Brazilian institutions targeting four distinct cardio­ pathies [6. Gabriel Rodriguez de Freitas Visiting Professor at the Instituto de Biofisica Carlos Chagas Filho. ƒƒ A prominent role of Brazilian Institutions and medical researchers in developing clinical trials using cell therapies under strict regulatory and ethical standards. (2012) 7(6 Suppl. which considers stem cells and cell therapies as an important area for the public health system in Brazil. Stevens Kastrup Rehen Professor at the Biomedical Institute of the Federal University of Rio de ­Janeiro. Research focus: embryonic stem cells Education: Medical doctor at Univer- sidade Federal Fluminense. With hundreds of stem cell researchers in Brazil. which demonstrated a satisfactory safety profile that led to the financing of an efficacy trial (to be started this year) in the aforementioned Brazil–Argentina cell therapy program.7] .Mendez-Otero & Campos de Carvalho Ones to watch. This report highlights three individuals.5] . Research focus: cell therapy in stroke and induced pluripotent stem cells.. ƒƒ The need to increase the incipient participation of private companies in the area. Institutes directly affiliated to the Ministry of Health in Rio de Janeiro. but not least. São Paulo. Rio de Janeiro and Minas Gerais States account for more than 70% of all research in this country. Brazilian research activity is highly concentrated in the southeast region. Two  influential articles published in the Journal of the American Medical Association described autologous bone marrow transplantation in Type I diabetes [4. the pioneering trial using bone marrow-derived cells in ischemic stroke [9–12] . PhD in the same University (2000). Universidade Federal do Rio de Janeiro. from various subdisciplines. research conducted by Brazilian groups has been prominent [3] . Lygia da Veiga Pereira Professor at the Biology Institute of the University of São Paulo.

431–440 (2011). or royalties. JAMA 297(14). Med . the References 1 Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. Burt RK. Cell Transplant. Sukoyan M. 11 Barbosa da Fonseca LM. Circulation 120(6). 244–253 (2009). Couri CE. Private companies The pharma and biotech sectors in Brazil are clearly under-represented in comparison to the size of the country’s economy. Dohmann HF. Martins MP. Loh Y. da Fonseca 4 LM et al. Gutfilen B.Brazil nent in conducting clinical trials of cell therapy in cardiac diseases (National Cardiology Institute) and in bone and cartilage defects (National Trauma and Orthopedic Institute) private sector has not been very active and there are few companies doing entrepeneurial activities in this field. Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study. 14 Tura BR. 21(Suppl. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing–remitting multiple sclerosis: a Phase I/II study.futuremedicine. 5(6). McMahon DS. 539–541 (2009). 2454–2461 (2012). Ribeiro Dos Santos R. stock ownership or options. Trials 9. Couri CE. Liver Int. Neurol . Feitosa G et al. de Freitas GR. Establishment of a Brazilian line of human embryonic stem cells in defined medium: implications for cell therapy in an ethnically diverse population.com 147 . Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intraarterial injection. 20(3). This includes employment. Cohen B et al. Thorsteinsdóttir H. Trials 8. consultancies. Transendocardial. 10 Battistella V. Borojevic R et al. 1). Martino HF. Araújo MD 8 3 et al. Early tissue distribution of bone marrow mononuclear cells after intra-arterial delivery in a patient with chronic stroke. Perin EC. da Fonseca LM „„ Website 101 Brazilian Network for Cell Therapy (Rede 6 Nacional de Terapia Celular [RNTC]) www. a spinoff from UFRJ. No writing assistance was utilized in the production of this manuscript. 2294–2302 (2003). Circulation 107(18). Bone marrow mononuclear cell therapy for patients with cirrhosis: a Phase 1 study. 13 Couto BG. Med . 1568–1576 (2007). Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed Type 1 diabetes mellitus. Multicenter double blind trial of autologous 7 bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction – MiHeart/AMI study. 31(3).org. 45–52 (2011). Barbosa da Fonseca LM. Regen. et al. Circulation 125(20). expert testimony. 6(1). Dohmann HF. grants or patents received or pending. Gowdak LH. 2 (2007). Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized trial of cell therapy in cardiopathies study): a multicenter randomized trial. 221(1). 391–400 (2011). Sousa AL et al. de Freitas GR et al. honoraria. Regenerative medicine in Brazil: small but innovative. 863–876 (2010). Chagas Arm of the MiHeart Study Investigators. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed Type 1 diabetes mellitus. JAMA 301(15). Most of them are associated with cord blood banks and a few are spin-offs associated with academia. dos 9 5 Santos RR et al. chronic ischemic heart failure. Battistella V. 12 Friedrich MA. Voltarelli JC. Lancet Neurol . autologous bone marrow cell transplantation for severe. Oliveira MC. S13–S21(2012). Following the trend. Regen. 122–128 (2010). 41 (2008). 2 Rosado de Castro PH et al. Fraga AM. 1573–1579 (2009).br future science group www. Besides Excellion and CellPraxys another private company investing in research and development has focused on developing reagents for stem cells is Hygeia. Exp. Daar AS. Stracieri AB et al. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke.rntc. Stracieri AB et al. 8(3). Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Rassi S. Goldenberg RC. Rajan P et al. Silva SA. Singer PA. Cell Transplant.

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Karolinska Institutet A medical university Karolinska Institutet is one of the world’s leading medical universities. Karolinska Institutet accounts for over 40 per cent of the medical academic research conducted in Sweden and offers the country´s broadest range of education in medicine and health sciences. Its mission is to contribute to the improvement of human health through research and education. Since 1901 the Nobel Assembly at Karolinska Institutet has selected the Nobel laureates in Physiology or Medicine.se Photo: Camilla Svensk . Visit us at ki.

Plan now.worldstemcellsummit. Take advantage of early registration discounts. and further explore what may be ahead. Save the Date: December 4-6. Sign up for the 2013 World Stem Cell Summit today and continue the journey. 2013 San Diego. Capitalize on your Summit experience. Secure the best arrangements. 2013 www. Together we’ll make a difference. Demonstrate your commitment to the growth and success of regenerative medicine.Continue the Journey Join us for the next World Stem Cell Summit December 4 – 6. Distill and incorporate what emerged. And make plans now to continue the dialogue at the 2013 World Stem Cell Summit. agendas and news.com . Help grow the field. California Build on the momentum. Receive advance notices of speakers. Add your voice and impact to developments – and to solutions – through participation and advocacy. Amplify your efforts by encouraging colleagues and organizations to join you at the 2013 Summit. Follow-up with colleagues.

com quoting CTB12 to claim your free trial Email us to claim your www.. Senior Editor ” 30-day FREE TRIAL Email us at info@futuremedicine.futuremedicine. Chris Mason..Your one-stop-shop “ for regenerative medicine information . a one-stop shop for regenerative medicine information.the very latest on the science.com . clinical translation and the regen industry.

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