The Pharmacologic Treatment of Fabry Disease

描述(申请人提供)：法布里病是一种X连锁疾病，具有不同的表型表达，包括显著的发病率和死亡率。死亡很大程度上是血管并发症的结果，包括中风和心肌梗塞。Fabry病通常被描述为一种基于病理的小血管病变，与球三糖神经酰胺(Gb3)过量的小血管闭塞一致。然而，血管并发症以及Gb3在溶血性尿毒症综合征发病机制中的作用表明，Gb3可能在涉及更大血管的动脉病理中发挥作用。令人惊讶的是，当α-半乳糖苷酶A基因敲除小鼠第一次被创造和表型时，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基因敲除小鼠中发现了一种动脉血管病变，其特征是强烈的血栓形成和血管扩张受损。在这些研究的基础上，提出了以下基本假设。法布里病的α-半乳糖苷酶A缺乏和球三糖神经酰胺积聚导致动脉血管病变。这种血管病变是由于激动剂通过非受体酪氨酸激酶刺激细胞信号的异常调节以及包括一氧化氮在内的血管活性化合物的形成受损所致。 提出了以下具体目标。 1.在体外模型系统中，确定球三糖神经酰胺含量的改变在刺激eNOS活性的激动剂所致的内皮细胞信号转导受损中的作用。 2.确定GLA-/0小鼠血管扩张缺陷的发生机制。 3.确定旨在消耗Globotriaosylceramide的治疗方法的有效性，包括底物抑制和重组α-半乳糖苷酶A给药在减轻Gla-/0小鼠血栓和血管活性缺陷方面的效果。 4.通过建立Gb3合酶基因敲除小鼠，评价三糖神经酰胺通过上位性作用在介导血栓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.