Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha -galactosidase A (alpha -gal A). This enzyme defici ency leads to impaired catabolism of alpha -galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and va scular occlusions that progressively lead to cardiovascular, cerebrovascula r, and renal dysfunction and early death. Although enzyme replacement thera py and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this d isease in humans. Delivery of the normal alpha -gal A gene (cDNA) into a de pot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombin ant adeno-associated viral vector encoding human alpha -gal A (rAAV-AGA) wa s constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha -gal A activity in the livers of rAAV-AGA-inject ed Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha -gal A levels in liver and other tissues co mpared with the untouched Fabry controls as long as 6 months after treatmen t. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no signi ficant immune response to the virus or alpha -gal A. Also, no signs of live r toxicity occurred after the rAAV-AGA administration. These findings sugge st that an AAV-mediated gene transfer may be useful for the treatment of Fa bry disease and possibly other metabolic disorders.