Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Look up keyword
Like this
1Activity
0 of .
Results for:
No results containing your search query
P. 1
UMSC-ALS

UMSC-ALS

Ratings: (0)|Views: 8|Likes:
Published by Torsak Tippairote

More info:

Published by: Torsak Tippairote on Jan 04, 2011
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

02/16/2014

pdf

text

original

 
© 2010 Coa and Slan, publshr and lcns Do Mdcal Prss Ltd. Ths s an Opn Accss artclhch prmts unrstrctd noncommrcal us, prodd th orgnal ork s proprly ctd.Stm Clls and Clonng: Adancs and Applcatons 2010:3 145–156
Stem Cells and Cloning: Advances and ApplicationsDovepress
submit your manuscript
145
Review
open access to scientifc and medical research
Opn Accss Full Txt Artcl
DOI:10.2147/SCCAA.S8662
Amyotrophc latral sclross: applcatonsof stm clls – an updat
Lda Coa
1
vncnzo Slan
2
1
Dpartmnt of Nurology andLaboratory of Nuroscnc, iRCCSisttuto Auxologco italano, Mlano,italy;
2
Dpartmnt of Nurology andLaboratory of Nuroscnc, “DnoFrrar” Cntr, Unrstà dgl Studd Mlano, iRCCS isttuto Auxologcoitalano, Mlano, italyCorrspondnc: vncnzo SlanDpartmnt of Nurology andLaboratory of Nuroscnc, “DnoFrrar” Cntr, Unrstà dgl Studd Mlano, iRCCS isttuto Auxologcoitalano, va Spagnoltto 3, 20149Mlano, italyTl
+
39 02 619112982Fax
+
Abstract:
Neurodegenerative diseases are a growing public health challenge, and amyotrophiclateral sclerosis (ALS) remains a atal incurable disease. The advent o stem cell therapy hasopened new horizons or both researchers and ALS patients, desperately looking or a treatment.ALS must be considered a systemic disease aecting many cell phenotypes besides motor neurons, even outside the central nervous system. Cell replacement therapy needs to addressthe specic neurobiological issues o ALS to saely and eciently reach clinical settings.Moreover, the enormous potential o induced pluripotent cells directly derived rom patients or modeling and understanding the pathological mechanisms, in correlation with the discoverieso new genes and animal models, provides new opportunities that need to be integrated with previously described transplantation strategies. Finally, a careul evaluation o preclinical datain conjunction with wary patient choice in clinical trials needs to be established in order togenerate meaningul results.
Keywords:
amyotrophic lateral sclerosis, regenerative medicine, stem cell therapy, clinical trials
Introduction
Amyotrophic lateral sclerosis (ALS) still remains, more than a century since rstdescription, a atal and untreatable disease. The use o pluripotent or multipotentcells or the restoration o damaged neuronal networks is one o the actors that holds promise rom a translational medicine perspective and a relevant part o the strongestorces driving research in stem cell (SC) biology applied to neurodegenerative diseases. Novel specic neuropathological ndings in ALS suggest a more generalized involve-ment outside the nervous system that needs to be ully evaluated beore strategies or replacement or rescue o damaged neurons can be urther developed.
Amyotrophic lateral sclerosis and thefrontotemporal involvement
ALS is a atal disease caused by the progressive loss o motor neurons (MNs) in boththe brain and the spinal cord leading to paralysis o voluntary muscles and death within2–5 years rom clinical onset.
1
Most cases o ALS are classied as sporadic ALS (sALS),albeit approximately 7%–10% are inherited in a dominant mode (amilial ALS [ALS]).
2
 Although several hypotheses have been proposed to explain the specic MN involvement,leading to their progressive degeneration, the underlying mechanisms remain elusive.
3
ALS has been considered to be the prototypical pyramidal motor system neuro-degenerative disease or decades. In terms o neuropathology, degeneration o theupper and lower motor neuron with MN cytoplasmic inclusions immunoreactive or 
Number of times this article has been viewed
This article was published in the following Dove Press journal:Stem Cells and Cloning: Advances and Applications22 October 2010
 
Stm Clls and Clonng: Adancs and Applcatons 2010:3
submit your manuscript
146
Coa and Slan
ubiquitin (U) and degeneration o the corticospinal tract wereconsidered to be diagnostic or ALS.
4
Recently, researchershave begun to recognize an important connection betweenrontotemporal dementia (FTD) and ALS or Lou Gehrig’sdisease (Figure 1A). FTD is a syndrome o progressivechanges in behavior, language, and cognition due to loss o unction o neurons in both the rontal and temporal lobes.Usually, FTD has relatively little eect on the parts o thenervous system that control movement, and so many FTD patients remain physically strong and relatively agile untillate in the illness. However, in approximately 10%–15% o  patients with FTD, the disease also involves the nerve cellscontrolling voluntary movement, the MNs. When this occurs,the syndrome is called FTD with motor neuron disease (FTD-MND). TDP-43 (ubiquitinated TAR DNA-binding protein)is a multiunctional DNA/RNA-binding actor that has beenimplicated in the regulation o neuronal plasticity.
5
The notionthat pathological TDP-43 is involved in neurological diseaseswas proposed when it was discovered by Neumann et al
6
sincethis protein has been identied as the major constituent o  pathological inclusions in FTD with U (FTD-U, now knownas FTD-TDP), FTD-MND, and ALS. Thereore, a common pathogenesis linked to TDP-43 abnormalities in these disor-ders has been suggested and urther conrmed.
5,7
This schemerelects the considerable overlap o clinicopathologicaleatures between all neurodegenerative diseases:
8
ALS,FTD-MND, and FTD-U may be situated at dierent pointsalong a continuous and broad spectrum o a multisystemicdegeneration
9,10
(Figure 1A). Recent ndings o mutationsin the
TARDBP
gene, encoding or TDP-43, in cases o autosomal-dominant ALS and rare sALS patients urther corroborate the signicance o pathological TPD-43 as being mechanistically implicated in the disease process.
11
 Patients with both FTD-MND and 
TARDBP
mutations have been reported.
12
Recently, it has been demonstrated thatelevated expression o TDP-43 in mouse orebrain causesneuropathological patterns similar to FTD-U, mimicking itsspecic behavior phenotype.
13
Moreover, both TDP-43 and 
STEM CELL THERAPY IN ALS
COMPREHENSION OF THEPATHOLOGICAL MECHANISMSEFFICIENTCLINICAL THERAPY A) CLINICALPATHOLOGICALOVERLAPSMND ALSFTDB) NEW GENES(i.e. RNA BINDINGPROTEINS)K) MULTISYSTEMICDISEASEL) IMPORTANCE OFPRE-CLINICALSTUDIES IN VITRO AND IN VIVOP) PILOT TRIALS+Q) NOVEL SURGICALTECHNIQUESR) INTERNATIONALGUIDELINES FORDRUG/SC TRIALS
CNSPNS
C) NOVEL ANIMALMODELSTDP-43, FUSvs SOD-IMiceH) POSTTRANSCRIPTIONAL AND EPIGENETICREGULATIONmiRNAmRNAsM) MN REPLACEMENTD) iPSPatient fibroblasts +Oct-4, Sox2,Klf-4, c-MyctransductionG) SC BASEDPLATFORMSCSCE) IN VITRODISEASEMODELSF) IN VITRODRUGSCREENINGI) ACTIVATION OFPATHOLOGICAL GENESJ) ALTERATION OFSC BIOLOGYO) ENDOGENOUSNEUROGENESISN) NEURORESCUE/NEUROPROTECTION
motorneuronmotorneuron
Figure 1
Nol “holstc” approach to ALS thrapy. Clncal orlaps btn ALS and othr nurodgnrat dsass could unral common molcular/pathologcalmchansms (A). Moror, n nsghts on causat gntc mutatons (B) and th dlopmnt of nol anmal modls (C) dn our knoldg of th possbl thraputctargts n th pathologcal pathays. in th mantm, rcnt PS tchnology (D) prods patnt-drd spcmns as dsas modlng and cll assays to dssct pathologcal
mechanisms and specic cell contribution (E). The development of SC-based therapies is also directly exploitable for new drug screening (F and G). The discovery of the
mportanc of pgntc rgulaton n th pathologcal procsss s parallld by a rlant rol n SC bology. Any altraton n ths complx ntork could altr SC dynamc
cross talk to the diseased surroundings, thus precluding possible therapeutic effects (H–J). The complex nature requires a multifaceted strategy, able to efciently contrastwidespread degeneration in all tissue districts (K), which should be carefully evaluated in accurate preclinical studies (L). Efcient therapeutic treatments are required both to
rplac MNs (M) and prod an halthy nronmnt for thm (N), capabl also of nhancng ndognous rpar (O). Ths laboratory studs ll lad to succssful clncal trals(P), basd on nol surgcal tchnqus (Q), abl to slo th dsas progrsson. Consnsus ntrnatonal gudlns for drug/SC trals ll guarant th conscntous translaton
of basic SC research into appropriate treatment applications for patients aiming to create optimized efcient protocols able to slow down (neuro)degeneration (R).
Abbreviations:
MND,
 
motor nuron dsas; ALS, amyotrophc latral sclross; FTD, frontotmporal dmnta; TDP-43, TAR DNA-bndng protn; FUS, fusd n sarcomaprotn; PS, nducd plurpotnt stm clls; Oct-4/Sox2/Klf-4/c-Myc, 4 transcrpton factors ssntal for PS gnraton; SC, stm cll; mRNA, mcro-RNA; MN, motornuron.
 
Stm Clls and Clonng: Adancs and Applcatons 2010:3
submit your manuscript
147
Applcaton of SCs n ALS
Cu/Zn superoxide dismutase-1 (SOD-1) proteins modulatesequestration o neurolament mRNAs in the aggregatescharacteristic in ALS MN degeneration.
14
Mutations in a gene encoding another DNA/RNA-binding protein with striking structural and unctional similarities toTDP-43 named FUS (used in sarcoma) or TLS (transloca-tion in liposarcoma) have been recently reported to trigger degeneration o MNs
15–17
and be responsible or FTD.
18
 Although this gene was initially identied as a componento a usion pro-oncogene resulting rom a chromosomaltranslocation seen in liposarcomas, it belongs similarly to asubamily o RNA-binding proteins, involved in MN (patho) physiological biology/metabolism (Figure 1B). Interestingly,FUS/TLS protein interacts with RNA, single-stranded DNA,and double-stranded DNA, and is involved in unique unc-tions in the mRNA processing and transport, transcriptionalregulation, and maintenance o genomic stability.
19
It has been also reported the selective presence o FUS
+
inclusionsin an elderly patient apparently not mutated in the gene butaected by MND.
20
The emerging scenario o multiple regional involve-ments due to the TDP-43/FUS neuropathological inclu-sions in the central nervous system (CNS) o ALS patientsentails a signicant impact on the therapeutic strategiesapplicable to them and, particularly, on the SC approach,since RNA-binding proteins appear as key regulators o signaling networks responsible or neuronal developmentand homeostasis,
21
as well as neural SC biology.
22
Thereore,healthy transplanted cells cross talk with the surroundingsmay also be compromised by the abnormal cellular RNAmetabolism, able to trigger MN degeneration, thus imped-ing any therapeutic outcomes. FUS and TDP-43 harbor alsoa “prion domain” very similar to the specic one present inseveral yeast prion proteins prone to pathological misoldingtransmissible within or between healthy cells or species. Inthis case, no SC strategy could maintain positive therapeuticoutcomes in the long term, without a supportive treatmentable to prevent the spread o the disease.
23
Moreover, merecell substitution appears insucient to contrast all the altera-tions in the interrelated complex pathways activated by ALS,as described in the ollowing paragraphs.
Stem cells and newpharmacotherapeutic strategies:approaching novel genes, diseasemodeling, and drug candidates
Additional interesting hints derive rom the discovery o thenovel pathological genes
TARDBP
6,24
and 
 FUS/TLS 
15
sincethey also have led to the derivation o new animal models,alternatives to the classic transgenic (tg) SOD-1, or deci- phering the mechanisms responsible or the motor systemneurodegeneration with large implications or SC therapiesin the CNS
25,26
(Figure 1C). In particular, it appears thatTDP-43 plays a pivotal role in many orms o MND, and this protein, being implicated in some orms o dementia,exerts a contributory role in a wider number o neurodegen-erative diseases.
27
Moreover, a careul examination o the pathological SCs in these new animal models, as well as o the surrounding niche, could reveal abnormalities that mayinfuence reparative mechanisms, as already suggested intgSOD-1 NPs,
28
wobbler mice,
29
and in the bone marrow o sporadic ALS patients.
30
Furthermore, remarkable pieces o inormation areexpected rom the recent generation o iPS cells (induced  pluripotent SCs, obtained by transducing cells with 4transcription actors: Oct-4, Sox2, Kl-4, and c-Myc;Figure 1D), deriving rom somatic tissues o an elderlyALS patient, which could be successully dierentiated toward well-characterized MNs.
31
iPS cells possess thesame advantages as traditional SCs due to their ability to produce dierentiated aected cells, such as neurons.
32
 However, the use o oncogenes and retrovirus in the currentiPS cell establishment protocol raises saety concerns sincetheir progeny show high teratoma-orming propensitiesthat actually restricts their potential use in cell therapy.
33
  Nevertheless, neurodegenerative disease-specic iPS may be used or assays with cell specimens uncollectible romlive patients (such as MNs, glial cells, and so on) to dis-sect their distinct peculiar infuence on pathological events(Figure 1E) and to dene new drug targets
34
(Figure 1F).Although reprogramming adult patient cells would be particularly interesting or both ALS and sALS, so ar noALS iPS-derived MNs appear to be aected by the disease.Conversely, both iPS cells rom spinal muscular atrophy
35
 (SMA) and amiliar dysautonomia,
36
characterized bychildhood onset, recapitulate all the pathological selectivedecits. Thereore, it appears that the complex interactions between genetic and environmental eatures combined tosenescence processes,
32
which are completely lacking duringiPS-derived MN dierentiation, may play a key role in ALSlate-onset degeneration. Additional long-term studies would  be necessary to recreate the correct pathophysiologicalconditions beore validation o this model or drug screeningor as a disease model or ALS.A precise dissection o the synergistic eects o SCimplantation on the ALS surroundings is limited by the

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->