Pharmacological chaperone therapy for Fabry disease.

Fabry disease is an inherited lysosomal storage disorder caused by deficient α-galactosidase A activity. Many missense mutations in Fabry disease often cause misfolded gene products, which leads to their retention in the endoplasmic reticulum by the quality control system; they are then removed by endoplasmic reticulum-associated degradation. We discovered that a potent α-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells. The oral administration of 1-deoxygalactonojirimycin to transgenic mice expressing human mutant α-galactosidase A resulted in significant increases in α-galactosidase A activity in various organs, with concomitant reductions in globotriaosylceramide, which contributes to the pathology of Fabry disease. Seventy-eight missense mutations were found to be responsive to 1-deoxygalactonojirimycin. These data indicate that many patients with Fabry disease could potentially benefit from pharmacological chaperone therapy.