The Validation of Pharmacogenetics for the Identification of Fabry Patients to Be Treated with Migalastat

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2016 Sep 23

PMID 27657681

Citations 100

Authors

Elfrida R Benjamin

Maria Cecilia Della Valle

Xiaoyang Wu

Evan Katz

Farhana Pruthi

Sarah Bond

Benjamin Bronfin

Hadis Williams

Julie Yu

Daniel G Bichet

Dominique P Germain

Roberto Giugliani

Derralynn Hughes

Raphael Schiffmann

William R Wilcox

Robert J Desnick

John Kirk

Jay Barth

Carrolee Barlow

Kenneth J Valenzano

Jeff Castelli

David J Lockhart

Affiliations

Soon will be listed here.

Abstract

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity.

Methods: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies.

Results: Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay.

Conclusion: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med 19 4, 430-438.

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