The Pharmacological Treatment of Fabry Disease

描述（由申请方提供）：法布里病是一种X连锁溶酶体贮积症，由遗传性α-半乳糖苷酶A（GLA）缺乏引起。该疾病的临床表现包括肾衰竭和心血管疾病，包括中风、心肌梗死和年轻至中年成人的充血性心力衰竭。虽然法布里病的患病率较低，但血管疾病的临床表现在法布里病人群中非常普遍，这表明这种疾病可能是了解更常见血管疾病发病机制的一个窗口。首先进行法布里病小鼠模型的研究，因为它们提供了用于证明葡糖神经酰胺合酶抑制剂治疗溶酶体贮积症的有效性的有用模型。最初，一系列葡糖神经酰胺合酶的小分子抑制剂被证明在GLA敲除小鼠中有效阻断神经酰胺三己糖苷的积累。一种这样的抑制剂将很快进入III期临床试验。尽管GLA敲除小鼠不会自发地发展出任何与法布里病中观察到的血管表型相当的血管表型，但随后的研究揭示了三种模拟人类疾病的血管病变的诱导实验模型。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受损的血管反应性。一个共同的机制，可以连接这些模型是受损的NO形成继发于eNOS解偶联。因此，GLA敲除小鼠不仅作为溶酶体贮积病的模型令人感兴趣，而且作为单基因疾病代表了用于研究更常见的大血管和微血管疾病的潜在重要模型。提出以下主要假设作为这些血管异常和受损GLA活性之间的机制联系：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。具体目标如下。首先，我们将确定NO生物活性降低的主要原因。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，我们将确定的组成和结构的糖突触的VEGF和胰岛素调节内皮细胞中的eNOS激活。公共卫生相关性：内皮细胞是血管中细胞的衬里层，是研究的一个重要焦点，旨在了解影响数百万人的血管疾病的科学基础。法布里病，这一建议的重点，是一种遗传性脂质储存疾病与中风和心脏病发作的过早发展。由于法布里病是由导致内皮功能障碍的单基因缺陷引起的，因此它为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.