Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice

Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human alpha-Gal A (rh alpha-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rh alpha-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rh alpha-Gal A via binding and stabilization. AT1001 prevented rh alpha-Gal A denaturation and activity loss in vitro at neutral pH and 37 degrees C. Coincubation of Fabry fibroblasts with rh alpha-Gal A and AT1001 resulted in up to fourfold higher cellular alpha-Gal A and similar to 30% greater GL-3 reduction compared to rh alpha-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rha-Gal A by > 2.5-fold, and in GLA knockout mice resulted in up to fivefold higher alpha-Gal A levels and fourfold greater GL-3 reduction than rh alpha-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rh alpha-Gal A, thus warranting clinical investigation.