title: A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease.
abstract: Fabry disease is caused by mutations in the gene (GLA) that encodes α-galactosidase A (α-Gal A). The iminosugar AT1001 (GR181413A, migalastat hydrochloride, 1-deoxygalactonojirimycin) is a pharmacological chaperone that selectively binds and stabilizes α-Gal A, increasing total cellular levels and activity for some mutant forms (defined as "responsive"). In this study, we developed a cell-based assay in cultured HEK-293 cells to identify mutant forms of α-Gal A that are responsive to AT1001. Concentration-dependent increases in α-Gal A activity in response to AT1001 were shown for 49 (60%) of 81 mutant forms. The responses of α-Gal A mutant forms were generally consistent with the responses observed in male Fabry patient-derived lymphoblasts. Importantly, the HEK-293 cell responses of 19 α-Gal A mutant forms to a clinically achievable concentration of AT1001 (10 µM) were generally consistent with observed increases in α-Gal A activity in peripheral blood mononuclear cells from male Fabry patients orally administered AT1001 during Phase 2 clinical studies. This indicates that the cell-based responses can identify mutant forms of α-Gal A that are likely to respond to AT1001 in vivo. Thus, the HEK-293 cell-based assay may be a useful aid in the identification of Fabry patients with AT1001-responsive mutant forms.
authors: Amicus Therapeutics, Cranbury, New Jersey 08512, USA.
authors: Xiaoyang
authors: X
authors: Wu
authors: Evan
authors: E
authors: Katz
authors: Maria Cecilia
authors: MC
authors: Della Valle
authors: Kirsten
authors: K
authors: Mascioli
authors: John J
authors: JJ
authors: Flanagan
authors: Jeffrey P
authors: JP
authors: Castelli
authors: Raphael
authors: R
authors: Schiffmann
authors: Pol
authors: P
authors: Boudes
authors: David J
authors: DJ
authors: Lockhart
authors: Kenneth J
authors: KJ
authors: Valenzano
authors: Elfrida R
authors: ER
authors: Benjamin
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