The Pharmacologic Treatment of Fabry Disease

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DESCRIPTION (provided by applicant): Fabry disease is an X-linked disorder with variable phenotypic expression that includes significant morbidity and mortality. The mortality is largely the result of vascular complications, including strokes and myocardial infarctions. Fabry disease has often been described as a small vessel vasculopathy based on pathology consistent with the occlusion of small vessels with excess globotriaosylceramide (Gb3). However, the vascular complications as well as the role of Gb3 in the pathogenesis of hemolytic uremic syndrome suggest that there may be a role for Gb3 in arterial pathology involving much larger blood vessels. Surprisingly, when alpha- galactosidase A knockout mice were first created and phenotyped, there was no obvious large or small vessel pathology observed. However, the applicant has recently identified an arterial vasculopathy in the alpha- galactosidase A knockout mouse marked by a robust thrombosis and impaired vasodilation. Based on these studies the following primary hypothesis is proposed. The alpha -galactosidase A deficiency and globotriaosylceramide accumulation in Fabry disease result in an arterial vasculopathy. This vasculopathy results from aberrant regulation of agonist stimulated cell signaling through non-receptor-tyrosine kinases and impaired formation vasoactive compounds including nitric oxide. The following Specific Aims are proposed. 1. Determine the role of altered globotriaosylceramide content in impaired endothelial cell signaling by agonists that stimulate eNOS activity in model in vitro systems. 2. Determine the mechanism for the vasodilatory defect in the Gla-/0 mouse. 3. Determine the efficacy of therapies designed to deplete globotriaosylceramide, including substrate inhibition and recombinant alpha -galactosidase A administration on mitigating the thrombotic and vasoactive defects in the Gla-/0 mouse. 4. Evaluate the role of globotriaosylceramide in mediating the altered thrombotic response and vasoactivity by epistasis with the creation of a Gb3 synthase knockout mouse.