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 (AAV9), 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. 5 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 (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the 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 the Fabry disease mouse model.

Fabry disease: Mechanism and therapeutics strategies

“…AAVs have been used to correct GLA gene deficiency in the CNS. A recent study explored the therapeutic benefit of AAV9 expressing human α-GLA in Fabry disease model mice ( Biferi et al, 2021 ). After a single intravenous injection, α-GLA activity was significantly increased in several tissues, including the CNS, compared with the control group.…”

Biopharmaceutical applications of α‐galactosidases

“…25 This ERT using α-galactosidase alleviates organ damage, stabilize renal or cardiac parameters, and assuage neuropathic pain crisis in FD patients. 18 Investigations are on the move to develop novel strategies to improve the efficacy of recombinant human α-Gal A 18,[26][27][28][29] and to prevent or alleviate clinical manifestations associated with long-term intervention of ERT. [30][31][32] Co-administration of α-galactosidase with migalastat HCl, a pharmacological chaperone, was found to significantly increase the tissue level activity of α-galactosidase.…”

“…In higher organisms, including man, α-galactosidases are found as intracellular enzymes and they hydrolyze the lysosomal storage carbohydrates. 18 Microbial α-galactosidases are robust and have attractive applications. According to the report by Marketysers Global Consulting LLP., New York City, USA, the global galactosidase market size was significantly vigorous in 2020.…”

Therapeutic Approaches in Lysosomal Storage Diseases

“…Although it is still unknown if the injection of AAV vectors can cover life-long expression of the transgene, preclinical studies have demonstrated that these vectors drive long-term expression of the transgene in animal models [ 62 ].…”