Fabry disease, an X-linked
glycosphingolipid storage disorder, is caused by the deficient activity of α-
galactosidase A (α-Gal A). This results in the lysosomal accumulation in various cell types of its
glycolipid substrates, including
globotriaosylceramide (GL-3) and lysoglobotriaosylceramide (globotriaosyl lysosphingolipid, lyso-GL-3), leading to kidney, heart, and
cerebrovascular disease. To
complement and potentially augment the current standard of care, biweekly infusions of recombinant α-Gal A, the merits of substrate reduction
therapy (SRT) by selectively inhibiting
glucosylceramide synthase (GCS) were examined. Here, we report the development of a novel, orally available GCS inhibitor (Genz-682452) with pharmacological and safety profiles that have potential for treating
Fabry disease. Treating Fabry mice with
Genz-682452 resulted in reduced tissue levels of GL-3 and
lyso-GL-3 and a delayed loss of the thermal nociceptive response. Greatest improvements were realized when the therapeutic intervention was administered to younger mice before they developed overt pathology. Importantly, as the pharmacologic profiles of α-Gal A and
Genz-682452 are different, treating animals with both drugs conferred the greatest efficacy. For example, because
Genz-682452, but not α-Gal A, can traverse the blood-brain barrier, levels of accumulated
glycosphingolipids were reduced in the brain of Genz-682452-treated but not α-Gal A-treated mice. These results suggest that combining substrate reduction and
enzyme replacement may confer both complementary and additive therapeutic benefits in
Fabry disease.