The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.
Genet Med
; 19(4): 430-438, 2017 04.
Article
in En
| MEDLINE
| ID: mdl-27657681
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.
Full text:
1
Database:
MEDLINE
Main subject:
Fabry Disease
/
1-Deoxynojirimycin
/
Alpha-Galactosidase
/
Mutation
Type of study:
Diagnostic_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Year:
2017
Type:
Article