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Stem Cell Reports. 2015 May 12;4(5):835-46. doi: 10.1016/j.stemcr.2015.02.022. Epub 2015 Apr 9.

Ex vivo gene therapy using patient iPSC-derived NSCs reverses pathology in the brain of a homologous mouse model.

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Research Institute of the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
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:


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.

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