The Pharmacological Treatment of Fabry Disease

描述(申请人提供)：法布里病是一种X连锁溶酶体储存障碍，由遗传缺陷的α-半乳糖苷酶A(GLA)引起。这种疾病的临床表现包括肾功能衰竭和心血管疾病，包括中风、心肌梗死和充血性心力衰竭，见于年轻人到中年人。虽然Fabry病的患病率很低，但血管疾病的临床表现在Fabry病人群中非常普遍，这表明该疾病可能是了解更常见的血管疾病发病机制的窗口。对Fabry病小鼠模型的研究最初是因为它们为证明葡萄糖神经酰胺合成酶抑制剂治疗溶酶体储存障碍的有效性提供了一个有用的模型。最初，一系列葡萄糖神经酰胺合成酶的小分子抑制剂被证明在GLA缺失的小鼠中有效地阻断了球三糖神经酰胺的积聚。一种这样的抑制剂将很快进入第三阶段临床试验。尽管GLA缺失的小鼠不会自发形成任何与Fabry病中观察到的血管表型相似的血管表型，但随后的研究揭示了三种可诱导的模拟人类疾病的血管病变实验模型。这些模型包括氧化剂诱导的血栓形成、加速的动脉粥样硬化形成和血管反应性受损。可能将这些模型联系在一起的一个共同机制是eNOS解偶联后继发NO的形成受阻。因此，GLA缺失小鼠不仅是溶酶体储存疾病的模型，而且是一种单基因疾病，对于更常见的宏观和微血管疾病的研究具有潜在的重要模型。以下主要假设被认为是这些血管异常和GLA活性受损之间的机制联系：在GLA缺乏的情况下观察到的血栓形成、致动脉粥样硬化和血管反应性异常是由于NO生物活性降低导致的内皮功能障碍的结果。具体目标包括以下几个方面。首先，我们将确定NO生物活性减弱的主要原因。其次，我们将确定Globo系列鞘糖脂在调节导致eNOS活性丧失的小窝的生物发生、结构和信号相关活动中的作用。第三，我们将确定控制血管内皮生长因子和胰岛素调节内皮细胞eNOS激活的糖突触的组成和结构。与公共卫生相关：血管内皮细胞是血管中细胞的衬里层，是旨在了解影响数百万人的血管疾病的科学基础的重要研究重点。这项提议的重点是法布里病，它是一种遗传性脂肪堆积疾病，与中风和心脏病发作的过早发展有关。由于法布里病是由单个基因缺陷导致的内皮功能障碍引起的，它为研究血管疾病的分子基础提供了一个独特的窗口。

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.