Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A
Résumé
Fabry disease is a rare X-linked disorder affectinga-galactosi-dase A, a rate-limiting enzyme in lysosomal catabolism of gly-cosphingolipids. Current treatments present important limita-tions, such as low half-life and limited distribution, which genetherapy can overcome. The aim of this work was to test a noveladeno-associated viral vector, serotype 9 (AAV9), ubiquitouslyexpressing humana-galactosidase A to treat Fabry disease(scAAV9-PGK-GLA). The vector was preliminary tested innewborns of a Fabry disease mouse model. 5 months after treat-ment,a-galactosidase A activity was detectable in the analyzedtissues, including the central nervous system. Moreover, wetested the vector in adult animals of both sexes at two dosesand disease stages (presymptomatic and symptomatic) by sin-gle intravenous injection. We found that the exogenousa-galactosidase A was active in peripheral tissues as well asthe central nervous system and prevented glycosphingolipidaccumulation in treated animals up to 5 months following in-jection. Antibodies againsta-galactosidase A were produced in9 out of 32 treated animals, although enzyme activity in tissueswas not significantly affected. These results demonstrate thatscAAV9-PGK-GLA can drive widespread and sustained expres-sion ofa-galactosidase A, cross the blood brain barrier aftersystemic delivery, and reduce pathological signs of the Fabrydisease mouse model.
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