title: Ex vivo gene therapy using patient iPSC-derived NSCs reverses pathology in the brain of a homologous mouse model.
abstract: Neural stem cell (NSC) transplantation is a promising strategy for delivering therapeutic proteins in the brain. We evaluated a complete process of ex vivo gene therapy using human induced pluripotent stem cell (iPSC)-derived NSC transplants in a well-characterized mouse model of a human lysosomal storage disease, Sly disease. Human Sly disease fibroblasts were reprogrammed into iPSCs, differentiated into a stable and expandable population of NSCs, genetically corrected with a transposon vector, and assessed for engraftment in NOD/SCID mice. Following neonatal intraventricular transplantation, the NSCs engraft along the rostrocaudal axis of the CNS primarily within white matter tracts and survive for at least 4 months. Genetically corrected iPSC-NSCs transplanted post-symptomatically into the striatum of adult Sly disease mice reversed neuropathology in a zone surrounding the grafts, while control mock-corrected grafts did not. The results demonstrate the potential for ex vivo gene therapy in the brain using human NSCs from autologous, non-neural tissues.
authors: Research Institute of the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Tagan A
authors: TA
authors: Griffin
authors: Research Institute of the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Hayley C
authors: HC
authors: Anderson
authors: Research Institute of the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; W.F. Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jhwolfe@vet.upenn.edu.
authors: John H
authors: JH
authors: Wolfe
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016538:Mucopolysaccharidosis VII / Q000628:therapy; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D039904:Pluripotent Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors