Je. Guidotti et al., Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice, HUM MOL GEN, 8(5), 1999, pp. 831-838
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.