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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.
AuthorsTagan A Griffin, Hayley C Anderson, John H Wolfe
JournalStem cell reports (Stem Cell Reports) Vol. 4 Issue 5 Pg. 835-46 (May 12 2015) ISSN: 2213-6711 [Electronic] United States
PMID25866157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Transcription Factors
Topics
  • Adult
  • Animals
  • Brain (pathology)
  • Cell Differentiation
  • Cells, Cultured
  • Cellular Reprogramming
  • Dependovirus (genetics)
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Humans
  • Karyotyping
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mucopolysaccharidosis VII (therapy)
  • Neural Stem Cells (cytology, metabolism, transplantation)
  • Pluripotent Stem Cells (cytology)
  • Transcription Factors (genetics, metabolism)

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