The Pharmacologic Treatment of Fabry Disease

描述（由申请人提供）：法布里病是一种X连锁疾病，具有可变的表型表达，包括显著的发病率和死亡率。死亡率主要是血管并发症的结果，包括中风和心肌梗塞。法布里病通常被描述为一种小血管病变，其病理学与过量神经酰胺三己糖苷（Gb 3）闭塞小血管一致。然而，血管并发症以及Gb 3在溶血性尿毒综合征发病机制中的作用表明，Gb 3可能在涉及大得多的血管的动脉病理学中发挥作用。令人惊讶的是，当α-半乳糖苷酶A敲除小鼠首次产生并进行表型分型时，没有观察到明显的大或小血管病理。然而，申请人最近在α-半乳糖苷酶A敲除小鼠中鉴定了以强烈的血栓形成和受损的血管舒张为标志的动脉血管病变。根据这些研究，提出了以下主要假设。法布里病中α-半乳糖苷酶A缺乏和神经酰胺三己糖苷蓄积导致动脉血管病变。这种血管病变是由激动剂刺激的细胞信号通过非受体酪氨酸激酶的异常调节和包括一氧化氮在内的血管活性化合物的形成受损引起的。 提出了以下具体目标。 1.在体外系统模型中，通过刺激eNOS活性的激动剂，确定改变的神经酰胺三己糖苷含量在受损内皮细胞信号传导中的作用。 2.确定Gla-/0小鼠血管舒张缺陷的机制。 3.确定旨在消耗神经酰胺三己糖苷的治疗（包括底物抑制和重组α-半乳糖苷酶A给药）对减轻Gla-/0小鼠血栓形成和血管活性缺陷的疗效。 4.评价神经酰胺三己糖苷在通过建立Gb 3合酶敲除小鼠的上位性介导血栓形成反应和血管活性改变中的作用。

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.