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A Pharmacogenetic Approach to Identify Mutant Forms of α-galactosidase A That Respond to a Pharmacological Chaperone for Fabry Disease

A Pharmacogenetic Approach to Identify Mutant Forms of α-galactosidase A That Respond to a Pharmacological Chaperone for Fabry Disease

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

Hum Mutat. 2011 Aug;32(8):965-77.

PMID: 21598360

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP73465437	1-Deoxymannojirimycin hydrochloride		73465-43-7	Price
AP75172815	Deoxygalactonojirimycin hydrochloride		75172-81-5	Price

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