EXPRESSION OF HUMAN BETA-HEXOSAMINIDASE ALPHA-SUBUNIT GENE (THE GENE DEFECT OF TAY-SACHS-DISEASE) IN MOUSE BRAINS UPON ENGRAFTMENT OF TRANSDUCED PROGENITOR CELLS

In humans, beta-hexosaminidase alpha-subunit deficiency prevents the f ormation of a functional beta-hexosaminidase A heterodimer resulting i n the severe neurodegenerative disorder, Tay-Sachs disease. To explore the feasibility of using ex vivo gene transfer in this lysosomal stor age disease, we produced ecotropic retroviruses encoding the human bet a-hexosaminidase alpha-subunit cDNA and transduced multipotent neural cell lines. Transduced progenitors stably expressed and secreted high levels of biologically active beta-hexosaminidase A in vitro and cross -corrected the metabolic defect in a human Tay-Sachs fibroblasts cell line in vitro. These genetically engineered CNS progenitors were trans planted into the brains of both normal fetal and newborn mice. Engraft ed brains, analyzed at various ages after transplant, produced substan tial amounts of human beta-hexosaminidase alpha-subunit transcript and protein, which was enzymatically active throughout the brain at a lev el reported to be therapeutic in Tay-Sachs disease. These results have implications for treating neurologic diseases characterized by inheri ted single gene mutations.