The Pharmacological Treatment of Fabry Disease

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DESCRIPTION (provided by applicant): Fabry disease is an X-linked lysosomal storage disorder resulting from the inherited deficiency in a-galactosidase A (GLA). Clinical manifestations of the disease include renal failure and cardiovascular disease, including strokes, myocardial infarction and congestive heart failure in young to middle aged adults. While the prevalence of Fabry disease is low, the clinical manifestations of vascular disease are highly prevalent in the Fabry disease population, suggesting that this disease may be a window to understanding the pathogenesis of more common vascular disorders. The study of mouse models of Fabry disease was first pursued because they provided a useful model for demonstrating the efficacy of glucosylceramide synthase inhibitors for the treatment of lysosomal storage disorders. Initially, a series of small molecule inhibitors of glucosylceramide synthase were demonstrated to be effective in the GLA null mouse in blocking the accumulation of globotriaosylceramide. One such inhibitor will soon enter phase III clinical trials. Although GLA null mice do not spontaneously develop any vascular phenotype comparable to that observed in Fabry disease, subsequent studies revealed three inducible experimental models of vasculopathy that mimic the human disease. These models include oxidant induced thrombosis, accelerated atherogenesis, and impaired vasoreactivity. A common mechanism that may link these models is impaired formation of NO secondary to eNOS uncoupling. Thus GLA null mouse is not only interesting as a model for lysosomal storage disease, but as a monogenic disorder represents a potentially important model for the study of more common macro and microvascular disease. The following primary hypothesis is proposed as the mechanistic link between these vascular abnormalities and impaired GLA activity: The thrombotic, proatherogenic, and vasoreactive abnormalities observed in the setting of GLA deficiency are the result of endothelial dysfunction due to decreased NO bio-activity. The specific aims include the following. First, we will determine the principal cause of diminished bio-activity of NO. Second, we will determine the role of globo series glycosphingolipids in regulating the biogenesis, structure, and signaling associated activities of caveolae that result in the loss of eNOS activity. Third, we will determine the composition and structure of the glycosynapse governing VEGF and insulin regulated eNOS activation in the endothelial cell. PUBLIC HEALTH RELEVANCE: The endothelium, the lining layer of cells in the blood vessels, is an important focus of research directed toward understanding the scientific basis for vascular diseases affecting millions of individuals. Fabry disease, the focus of this proposal, is an inherited lipid storage disease associated with the premature development of strokes and heart attacks. Because Fabry disease results from a single gene defect resulting in endothelial dysfunction, it provides a unique window on the molecular basis for vascular disease.