Optimizing human α-galactosidase for treatment of Fabry disease.

ABSTRACT: Fabry disease is caused by a deficiency of α-galactosidase A (GLA) leading to the lysosomal accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids. Fabry patients experience significant damage to the heart, kidney, and blood vessels that can be fatal. Here we apply directed evolution to generate more stable GLA variants as potential next generation treatments for Fabry disease. GLAv05 and GLAv09 were identified after screening more than 12,000 GLA variants through 8 rounds of directed evolution. Both GLAv05 and GLAv09 exhibit increased stability at both lysosomal and blood pH, stability to serum, and elevated enzyme activity in treated Fabry fibroblasts (19-fold) and GLA^-/- podocytes (10-fold). GLAv05 and GLAv09 show improved pharmacokinetics in mouse and non-h

SUBMITTER: Hallows WC 

PROVIDER: S-EPMC10036536 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature