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[Byer, Stephen] 
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Cytotherapy
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Stem-cell transplantation into the frontal motor cortex in amyotrophic lateralsclerosis patients
Hector R. Martinez
abc
; Maria T. Gonzalez-Garza
c
; Jorge E. Moreno-Cuevas
c
; Enrique Caro
d
; EugenioGutierrez-Jimenez
ac
; Jose J. Segura
aa
Servicio de Neurologia, Hospital Universitario UANL,
b
Hospital San Jose Tec de Monterrey, Servicio deNeurologia
c
Tecnologico de Monterrey, School of Medicine, Servicio de Terapia Celular, CITES,
d
Servicio deNeurocirugia, Hospital San Jose Tec de Monterrey, Monterrey, MexicoFirst Published:February2009
To cite this Article
Martinez, Hector R., Gonzalez-Garza, Maria T., Moreno-Cuevas, Jorge E., Caro, Enrique, Gutierrez-Jimenez,Eugenio and Segura, Jose J.(2009)'Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosispatients',Cytotherapy,11:1,26 — 34
To link to this Article: DOI:
10.1080/14653240802644651
URL:
http://dx.doi.org/10.1080/14653240802644651
Full terms and conditions of use:http://www.informaworld.com/terms-and-conditions-of-access.pdfThis article may be used for research, teaching and private study purposes. Any substantial orsystematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply ordistribution in any form to anyone is expressly forbidden.The publisher does not give any warranty express or implied or make any representation that the contentswill be complete or accurate or up to date. The accuracy of any instructions, formulae and drug dosesshould be independently verified with primary sources. The publisher shall not be liable for any loss,actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directlyor indirectly in connection with or arising out of the use of this material.
 
Stem-cell transplantation into the frontal motorcortex in amyotrophic lateral sclerosis patients
Hector R. Martinez
1,2,3
, Maria T. Gonzalez-Garza
3
, Jorge E. Moreno-Cuevas
3
,Enrique Caro
4
, Eugenio Gutierrez-Jimenez
1,3
and Jose J. Segura
1
1
Servicio de Neurologia, Hospital Universitario UANL,
2 
Servicio de Neurologia, Hospital San Jose Tec de Monterrey,
3 
Tecnologico de Monterrey,School of Medicine, Servicio de Terapia Celular, CITES, and 
4 
Servicio de Neurocirugia, Hospital San Jose Tec de Monterrey, Monterrey, Mexico 
Background aims
 Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons. CD133 
'
stem cells are known to have the capacity to differentiate into neural lineages. Stem cells may provide an alternative treatment for ALS and other neurodegenerative diseases.
Methods
Five men and five women (aged 38 
 Á 
62 years) with confirmed ALS were included in this study. Our institutional ethics and research committees approved the protocol. After informed consent was obtained, patients underwent Hidrogen-Magnetic Resonance Imaging (H-MRI)spectroscopy and were given scores according to an ALS functional rating scale, Medical Research Council power muscle scale and daily living activities. Bone marrow was stimulated with 300 
m
 g filgrastim subcutaneously daily for 3 days. Peripheral blood mononuclear cells were obtained after admission by leukapheresis. The cell suspension was conjugated with anti-human CD133 superparamagnetic microbe-ads, and linked cells were isolated in a magnetic field. The isolated cells (2.5 
 Á 
7.5 
)
10 
5 
 ) were resuspended in 300 
m
L of the patient’s cerebrospinal fluid, and implanted in motor cortexes using a Hamilton syringe. Ten patients with confirmed ALS without transplantation were used as a control group. Patients were followed up for a period of  1 year.
Results
The autologous transplantation of CD133 
'
stem cells into the frontal motor cortex is a safe and well-tolerated procedure in ALS patients.The survival of treated patients was statistically higher ( 
P 
0
0.01) than untreated control patients.
Conclusions
Stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life.
Keywords
 Amyotrophic lateral sclerosis, autologous transplant, CD133, neurode- generative disorders, stem cells.
Introduction 
Amyotrophic lateral sclerosis (ALS) is a late-onset neuro-degenerative disorder characterized by rapid deteriorationand selective death of motor neurons in the cerebral cortex,brain stem and spinal cord [1
 Á 
3]. A wide variety of clinicalfeatures are present early in the course of ALS [4]. There isno specific diagnostic test, although a clinical diagnosis of ALS is probably correct in more than 95% of cases [5].Sometimes it is difficult to separate ALS from other motorneuron diseases, such as Kennedy’s disease, monomelicamyotrophy, X-linked spinobulbar muscular atrophy andcervical spondylotic myelopathy [4,5]. Formal criteria areused for clinical trials but these may be too restrictive, assome patients die of ALS without qualifying for atherapeutic trial. The median survival of ALS patients isusually 29.1 months after presentation [6] and, despiteexciting advances in understanding the molecular basis of ALS,theetiologyofsporadiccases remainsunexplained[4].There is only one medication approved by the FDA totreat ALS. However, this drug is expensive and only delays
Correspondence to: 
Hector R. Martinez
, MD, FACP, Escuela de Medicina, CITES, 3
a
Piso, Morones Prieto 3000 Pte, Col. Doctores, CP 64710,Monterrey, NL Mexico. E-mail: drhectormtz@yahoo.comCytotherapy (2009) Vol. 11, No. 1, 26
 Á 
34
–
2009 ISCT 
DOI: 10.1080/14653240802644651
 D o w nl o ad ed  B y : [ B y e r ,  S t e ph e n]  A t : 17 :38 1  M a r ch 2009
 
disease progression modestly [4]. Stem-cell therapy isconsidered to be an alternative method for treating ALSand other neurodegenerative disorders [7
 Á 
10]. Stem-celltransplantation is a potential therapeutic strategy not onlyvia cell replacement but also by modification of theextracellular motor neuronal environment, through atrophic and neuroprotective effect [11]. A variety of cellsources have been considered for cell therapy, includingneural stem cells, embryonic stem cell-derived neuronsand somatic stem cells, such as hematopoietic stem cells[12
 Á 
15]. In SOD1 transgenic mice, an experimental modelthat resembles ALS, the transplantation of hematopoieticstem cells from murine bone marrow (BM) or from humancord blood cells increased the animals’ lifespan [13].However, at present, no animal model reproduces all of the salient features of ALS, particularly the involvement of corticospinal and corticobulbar tracts [13
 Á 
15]. CD133 is astem-cell glycoprotein antigen selectively expressed onprogenitor cells [16,17]. These cells have been isolatedfrom different sources, such as BM, peripheral blood andumbilical cord, and are known to have the capacity todifferentiate into several lineages, including cardiac,endothelial, hepatic and neural lineages [12
 Á 
19]. It hasbeen demonstrated by several groups that stem cellsisolated from human BM can be induced to differentiateinto neurons. Reports indicate that these differentiatedcells express nestin, neuron-specific enolase, neuron-specific nuclear protein, glial fibrillary acidic protein,neurofilaments, Tau, Nurr1 and neuron-specific tubulin-1 [20
 Á 
24]. An additional report has described these cellsdisplaying synaptic transmission capabilities [25]. Finally,
in vivo 
models in rodents have demonstrated that systemictransplantation of human BM-derived CD133
'
cellsdisplays migration, engraftment and improvement of neurologic deficits [26,27].Clinical studies using stem cells in humans have beendescribed for Huntington’s disease, Parkinson’s disease,complete spinal cord injury, stroke patients and Batten’sdisease [28
 Á 
32]. Recently, a method of intraspinal cordimplantation of autologous hematopoietic stem cellsin patients with confirmed ALS was described, and theauthors reported this method as safe [10]. Another studyhas assessed the safety and therapeutic efficacy of autologous human BM stromal cell transplantation in35 complete spinal cord injury patients [30
 Á 
32]. To assessboth safety and efficacy, we have performed an uncon-trolled, open-label non-randomized clinical trial usingautologous CD133
'
stem-cell transplantation into thefrontal motor cortex of confirmed ALS patients. Thescientific rationale for our clinical research was thatCD133
'
stem cells obtained from peripheral blood arecapable of differentiating into neurons, and their trans-plantation into the frontal motor cortex was aimed atimproving upper motor neuron function.
Methods 
Study subjects
All patients were recruited and evaluated for eligibility atthe neurology service of the Hospital Universitario UANL,Monterrey, Mexico, and the Neurosciences Center of theHospital San Jose Tec de Monterrey, Monterrey, Mexico,from June 2005 to December 2006. The ethics and researchcommittees of the Hospital San Jose Tec de Monterreyand the Tecnolo´gico de Monterrey School of Medicine,Monterrey, Mexico, approved the protocol, and all theparticipating patients signed an informed consent form. Atrained neurologist conducted examinations for the diag-nosis of ALS, which was made using the well-establishedEl Escorial criteria [33,34]. Patients who had signed theconsent form and who had had a definite diagnosis of ALSfor more than 1 year and less than 4 years were enrolled inthe study. Patients with a current, or past, history of neurologic disease other than ALS, and those enrolled inother clinical trials, were excluded. The approval by ethicsand research committees was set strictly at 10 patientsinitially, and they suggested close monitoring of the safetyof the procedure. The follow-up period in the study forALS cases and controls ended in February 2008.The inclusion criteria for patients were: (a) confirmedALS according to the El Escorial clinical and neurophy-siologic criteria; (b) cervical and cranial magnetic reso-nance imaging (MRI) excluding structural damage to thebrain and spinal cord; (c) a functional respiratory testshowing the occurrence of forced vital capacity (FVC)values; and (d) an appropriate nutritional state (above20%). Exclusion criteria were: (a) severe bulbar involve-ment; (b) an inadequate nutritional state; (c) tracheostomyor gastrostomy; (d) the presence of systemic disorders,such as malignant neoplasm, cardiovascular disease, pre-vious stroke or coagulation abnormalities; and (e) evidenceof cervical spondylotic myelopathy or structural abnorm-alities by MRI.Confirmed ALS patients complying with the inclusioncriteria who did not accept treatment, or who applied after
Stem-cell transplantation in ALS 27
 D o w nl o ad ed  B y : [ B y e r ,  S t e ph e n]  A t : 17 :38 1  M a r ch 2009
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