Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice

The severe neurodegenerative disorder, Tays-Sachs disease, is caused by a b eta-hexosaminidase alpha-subunit deficiency which prevents the formation of lysosomal heterodimeric alpha-beta enzyme, hexosaminidase A (HexA), No tre atment is available for this fatal disease; however, gene therapy could rep resent a therapeutic approach. We previously have constructed and character ized, in vitro, adenoviral and retroviral vectors coding for alpha- and bet a-subunits of the human beta-hexosaminidases. Here, we have determined the in vivo strategy which leads to the highest HexA activity in the maximum nu mber of tissues in hexA-deficient knock-out mice. We demonstrated that intr avenous co-administration of adenoviral vectors coding for both alpha- and beta-subunits, resulting in preferential liver transduction, was essential to obtain the most successful results. Only the supply of both subunits all owed for HexA overexpression leading to massive secretion of the enzyme in serum, and full or partial enzymatic activity restoration in all peripheral tissues tested. The enzymatic correction was likely to be due to direct ce llular transduction by adenoviral vectors and/or uptake of secreted HexA by different organs. These results confirmed that the liver was the preferent ial target organ to deliver a large amount of secreted proteins. In additio n, the need to overexpress both subunits of heterodimeric proteins in order to obtain a high level of secretion in animals defective in only one subun it is emphasized, The endogenous non-defective subunit is otherwise limitin g.