Co-administration with the pharmacological chaperone AT1001 increases recombinant human ?-galactosidase A tissue uptake and improves substrate reduction in Fabry mice.

ABSTRACT: Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase ?-galactosidase A (?-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human ?-Gal A (rh?-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rh?-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?-Gal A via binding and stabilization. AT1001 prevented rh?-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rh?-Gal A and AT1001 resulted in up to fourfold higher cellular ?-Gal A and ~30% greater GL-3 reduction compared to rh?-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rh?-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher ?-Gal A levels and fourfold greater GL-3 reduction than rh?-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rh?-Gal A, thus warranting clinical investigation.

SUBMITTER: Benjamin ER 

PROVIDER: S-EPMC3321591 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature