The Pharmacological Treatment of Fabry Disease

描述（由申请人提供）：法布里病是一种由遗传的A -半乳糖苷酶A （GLA）缺乏引起的x连锁溶酶体贮积症。该病的临床表现包括肾衰竭和心血管疾病，包括中青年中风、心肌梗死和充血性心力衰竭。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，这表明该疾病可能是了解更常见血管疾病发病机制的窗口。法布里病小鼠模型的研究首先被进行，因为它们提供了一个有用的模型来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功效。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可以有效地阻断GLA缺失小鼠的globotriaosylneuroide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缺失小鼠不会自发地产生任何与法布里病观察到的血管表型相媲美的血管表型，但随后的研究揭示了三种模拟人类疾病的血管病变诱导实验模型。这些模型包括氧化诱导的血栓形成、加速的动脉粥样硬化和受损的血管反应性。可能将这些模型联系起来的一个共同机制是eNOS解耦引起的NO形成受损。因此，GLA缺失小鼠不仅是溶酶体贮积病的有趣模型，而且作为一种单基因疾病，代表了研究更常见的大血管和微血管疾病的潜在重要模型。以下主要假设是这些血管异常与GLA活性受损之间的机制联系：GLA缺乏情况下观察到的血栓形成、动脉粥样硬化和血管反应性异常是由于NO生物活性降低引起的内皮功能障碍的结果。具体目标包括以下内容。首先，我们将确定一氧化氮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活性丧失的小泡的生物发生、结构和信号相关活动中的作用。第三，我们将确定控制内皮细胞中VEGF和胰岛素调节的eNOS激活的糖突触的组成和结构。公共卫生相关性：内皮，即血管细胞的内层，是研究的重要焦点，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，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.