A pharmacogenetic approach to identify mutant forms of α-galactosidase a that respond to a pharmacological chaperone for Fabry disease
✍ Scribed by Xiaoyang Wu; Evan Katz; Maria Cecilia Della Valle; Kirsten Mascioli; John J. Flanagan; Jeffrey P. Castelli; Raphael Schiffmann; Pol Boudes; David J. Lockhart; Kenneth J. Valenzano; Elfrida R. Benjamin
- Book ID
- 102260667
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 489 KB
- Volume
- 32
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
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. Hum Mutat 32:1–13, 2011. © 2011 Wiley-Liss, Inc.