Recent studies from our laboratory and others suggest that murine hematopoietic stem cells and perhaps other cell populations derived from non-hematopoietic organs, may possess the capacity to differentiate into a range of mature cell types distinct from those originally thought to be derived from the cells. This apparent 'plasticity' of stem cell populations offers new opportunities to expand the use of bone marrow transplantation, in conjunction with gene transfer, to treat congenital diseases which affect cells other than those of the blood. Such a strategy may be particularly important for the treatment of diseases in which the systemic delivery of cells or genes throughout the body is essential, such as muscular dystrophy. In this research program, we propose to (i) determine, in a comprehensive way, the spectrum of cell types than can be derived from different populations of stem cells isolated from the adult, (ii) to develop procedures for the isolation, manipulation, and transplantation of cells which lead to the optimized production and systemic engraftment of specific cell types, and (iii) to apply those procedures, along with the methods we have previously developed for the transduction of hematopoietic stem cells, to the evaluation of gene therapies for the treatment of specific congenital disease, using well characterized animal models.
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