Systemic treatment of Fabry disease using a novel AAV9 vector expressing α-Galactosidase A

Abstract Fabry disease is a rare X-linked disorder affecting α-Galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel Adeno-Associated viral vector, serotype 9, ubiquitously expressing human α-Galactosidase A to treat Fabry Disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry Disease mouse model. Five months after treatment, α-Galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (pre-symptomatic and symptomatic), by single intravenous injection. We found that the exogenous α-Galactosidase A was active in peripheral tissues as well as central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-Galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-Galactosidase A, cross the blood brain barrier after systemic delivery and reduce pathological signs of Fabry Disease mouse model.