Abstract
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.
Highlights
Fabry disease is an X-linked inherited metabolic disorder caused by the deficient activity of the lysosomal hydrolase α-galactosidase A (α-Gal A) [1]
Enzyme replacement therapy has been shown to be highly effective in correcting the disease manifestations of several lysosomal storage disorders including type 1 Gaucher, Pompe, mucopolysaccharidosis I (MPS I) and Fabry disease [16]
The lipids that accumulate in endothelial cells of Fabry disease are efficiently cleared by rh α-Gal A, other cell types such as the glomerular podocytes and cardiomyocytes are reportedly less responsive to enzyme therapy [9,35,36] unless treatment starts early [10]
Summary
Fabry disease is an X-linked inherited metabolic disorder caused by the deficient activity of the lysosomal hydrolase α-galactosidase A (α-Gal A) [1]. Progressive lysosomal accumulation of globotriaosylceramide (GL-3) and related glycolipid substrates leads to a number of clinical manifestations that define the two major Fabry disease phenotypes. The early-onset, severe “classic” Type 1 phenotype has little (1%) and no microvascular endothelial substrate accumulation or early Type 1 manifestations, but it progresses to renal and cardiac disease, typically during or after the third decade of life [1]. It should be noted that the rate and extent of clearance varies, with some cell types in the kidney (podocytes and distal tubular epithelial cells) and heart (cardiomyocytes) being more refractory to treatment [9]
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