The natural ability of neural stem cells (NSCs) to migrate within the brain, under certain circumstances, has long made them a candidate for treatment of CNS diseases. The development of methods to reprogram human somatic cells into tissue specific stem cells has provided great hope for using NSC therapies for many brain disorders. NSC transplantation experiments in mouse models of human diseases have demonstrated correction of at least some pathology in several types of diseases, providing proof-of-principle for the NSC- based approach. However, a significant barrier to effective translation is the low level of engraftment that occurs. Neurogenetic diseases have globally distributed lesions in the CNS due to the nature of the defect, thus treatment requires disseminated distribution of the donor cells. Achieving that will, however, require much better understanding of the post-transplantation properties of NSCs. We have reprogrammed human patient fibroblasts into pluripotent stem cells (iPSCs), derived NSCs from them, and genetically corrected the hu-iPS- NSCs. We propose xenograft studies to evaluate the effects of engineering hu-iPS-NSCs on post-transplant distribution and survival. We will test the therapeutic effectiveness of delivering a diffusible protein within the brain, in a well-characterized mouse model of a human lysosomal storage disease (LSD). There are >50 individual LSDs and they are responsible for a large portion of all inherited childhood genetic diseases that affect the CNS. A common treatment strategy can be used, in principle, for most of the LSD's, based on the observation that lysosomal enzymes are exported from genetically corrected cells and taken up by mutant cells to restore the missing enzymatic activity. Preliminary studies indicate the hu-iPS-NSCs engraft in the NOD- SCID mouse brain at low levels. The proposed experiments will investigate basic features of post-transplant dispersion and survival of the donor cells to address the problem of inadequate NSC engraftment. We have obtained compelling preliminary data demonstrating the feasibility of the proposed experiments and we will use quantitative analyses to measure amounts of engraftment, differentiation into mature neural cell types, and changes in pathology. The long-term strategy of this line of research is to develop NSC transplants in the mouse brain to a level where they can be tested in large animal models of brain diseases in future translational studies and eventually into the human brain which is ~3,000 times larger than the mouse brain. It is clear that progress on this problem needs significant advances in understanding the biology of NSC engraftment and development of strategies to enhance engraftment.

Public Health Relevance

This grant will investigate strategies to achieve improved delivery of therapeutic neural stem cells (NSCs) in the in the brain by exploiting the migratory properties of NSCs. The focus is on reprogrammed patient-specific human NSCs. The long-term goal is to develop treatments for human genetic diseases that affect the brain, most of which do not have adequate therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Lavaute, Timothy M
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Children's Hospital of Philadelphia
Independent Hospitals
United States
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Griffin, Tagan A; Anderson, Hayley C; Wolfe, John H (2015) Ex vivo gene therapy using patient iPSC-derived NSCs reverses pathology in the brain of a homologous mouse model. Stem Cell Reports 4:835-46