A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke.
Transplantation of neural stem cells into the brain is a novel approach to the treatment of chronic stroke disability. For clinical application, safety and efficacy of defined, stable cell lines produced under GMP conditions are required. To this end, a human neural stem cell line, CTX0E03, was derived from human somatic stem cells following genetic modification with a conditional immortalizing gene, c-mycER(TAM). This transgene generates a fusion protein that stimulates cell proliferation in the presence of a synthetic drug 4-hydroxy-tamoxifen (4-OHT). The cell line is clonal, expands rapidly in culture (doubling time 50-60 h) and has a normal human karyotype (46 XY). In the absence of growth factors and 4-OHT, the cells undergo growth arrest and differentiate into neurons and astrocytes. Transplantation of CTX0E03 in a rat model of stroke (MCAo) caused statistically significant improvements in both sensorimotor function and gross motor asymmetry at 6-12 weeks post-grafting. In addition, cell migration and long-term survival in vivo were not associated with significant cell proliferation. These data indicate that CTX0E03 has the appropriate biological and manufacturing characteristics necessary for development as a therapeutic cell line.
Pollock
Kenneth
K
ReNeuron Ltd., 10 Nugent Road, Surrey Research Park, Guildford, Surrey GU2 7AF, UK.
Stroemer
Paul
P
Patel
Sara
S
Stevanato
Lara
L
Hope
Andrew
A
Miljan
Erik
E
Dong
Ziping
Z
Hodges
Helen
H
Price
Jack
J
Sinden
John D
JD
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D002999:Clone Cells; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D006801:Humans; D006915:Hydroxytestosterones / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000601:surgery*; D008297:Male; D009043:Motor Activity / Q000502:physiology; D046569:Neuroepithelial Cells / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D019098:Telomerase / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods
D006915:Hydroxytestosterones; D012333:RNA, Messenger; C032278:4,17 beta-dihydroxy-4-androstene-3-one; D019098:Telomerase