[Chaperone molecules: The example of Fabry disease]

Fabry disease is due to mutations in the GLA gene that cause a deficiency of the activity of the lysosomal enzyme alpha-galactosidase A (α-gal A) resulting in intra-tissue accumulation of globotriaosylceramide. Recently, a novel therapeutic approach based on the pharmacological chaperone migalastat has been developed. It binds, in a specific and reversible manner, to the catalytic site of α-gal A mutants, to prevent their degradation by the quality control system of the endoplasmic reticulum and allow them to catabolize globotriaosylceramide in the lysosomes. This treatment concerns approximately 35% of the GLA gene mutations recognized as sensitive to migalastat according to an in vitro pharmacogenetic test. Two pivotal Phase III studies, FACETS: migalastat vs. placebo and ATTRACT: migalastat vs. enzyme replacement therapy analyzed the in vivo effects of migalastat. Despite some methodological limitations, promising results were found. Migalastat seems to be more effective than enzyme replacement therapy in reducing left ventricular mass index in case of cardiac hypertrophy and has comparable renal effects. This oral treatment is the first personalized treatment, based on the genetic profile of Fabry patients and opens a new era in the management of conformational diseases.