Expression of human −hexosaminidase −subunit gene (the gene defect of Tay−Sachs disease) in mouse brains upon engraftment of transduced progenitor cells

In humans, −hexosaminidase −subunit deficiency prevents the formation of a functional −hexosaminidase A heterodimer resulting in the severe neurodegenerative disorder, Tay−Sachs disease. To explore the feasibility of using ex vivo gene transfer in this lysosomal storage disease, we produced ecotropic retroviruses encoding the human −hexosaminidase −subunit cDNA and transduced multipotent neural cell lines. Transduced progenitors stably expressed and secreted high levels of biologically active −hexosaminidase A in vitro and cross−corrected the metabolic defect in a human Tay−Sachs fibroblasts cell line in vitro. These genetically engineered CMS progenitors were transplanted into the brains of both normal fetal and newborn mice. Engrafted brains, analyzed at various ages after transplant, produced substantial amounts of human −hexosaminidase −subunit transcript and protein, which was enzymatically active throughout the brain at a level reported to be therapeutic in Tay−Sachs disease. These results have implications for treating neurologic diseases characterized by inherited single gene mutations.

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