The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

被引：179

作者：

Benjamin, Elfrida R. ^{[1
]}

Della Valle, Maria Cecilia ^{[1
]}

Wu, Xiaoyang ^{[1
]}

Katz, Evan ^{[1
]}

Pruthi, Farhana ^{[1
]}

Bond, Sarah ^{[2
]}

Bronfin, Benjamin ^{[2
]}

Williams, Hadis ^{[1
]}

Yu, Julie ^{[1
]}

Bichet, Daniel G. ^{[3
]}

Germain, Dominique P. ^{[4
]}

Giugliani, Roberto ^{[5
]}

Hughes, Derralynn ^{[6
]}

Schiffmann, Raphael ^{[7
]}

Wilcox, William R. ^{[8
]}

Desnick, Robert J. ^{[9
]}

Kirk, John ^{[1
]}

Barth, Jay ^{[1
]}

Barlow, Carrolee ^{[1
,10
]}

Valenzano, Kenneth J. ^{[1
]}

Castelli, Jeff ^{[1
]}

Lockhart, David J. ^{[1
,11
]}

机构：

[1] Amicns Therapeut, Cranbury, NJ 08512 USA

[2] Cambridge Biomed, Boston, MA USA

[3] Univ Montreal, Hop Sacre Coeur, Montreal, PQ, Canada

[4] Univ Paris Saclay, Univ Versailles, Div Med Genet, Montigny, France

[5] HCPA UFRGS, Med Genet Serv, Porto Alegre, RS, Brazil

[6] UCL, Royal Free Campus, London, England

[7] Baylor Res Inst, Dallas, TX USA

[8] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA

[9] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[10] Parkinsons Inst & Clin Ctr, Sunnyvale, CA USA

[11] TranscripTx Inc, Sunnyvale, CA USA

来源：

GENETICS IN MEDICINE | 2017年 / 19卷 / 04期

关键词：

enzyme replacement therapy; Fabry disease; lysosomal storage disorder; personalized medicine; pharmacological chaperone; ALPHA-GALACTOSIDASE; PHARMACOLOGICAL CHAPERONE; ENZYME REPLACEMENT; DISEASE; SAFETY; MUTATIONS; CLEARANCE; PHENOTYPE; DISORDER; CORRECTS;

D O I：

10.1038/gim.2016.122

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the a-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of a-galactosidase A to restore lysosomal activity. Methods: A phannacogenetic assay was used to identify the a-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease causing mutations were expressed in HEK-293 (HEK) cells; increases in a-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 a-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.

引用

页码：430 / 438

页数：9

共 34 条

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