The Pharmacological Treatment of Fabry Disease

摘要 法布里病是一种X连锁的溶酶体贮积症， 遗传性半乳糖苷酶A（GLA）缺乏症。临床表现 疾病包括肾衰竭和心血管疾病，包括中风， 心肌梗死和充血性心力衰竭。 虽然法布里病的患病率较低，但其临床表现 血管疾病在法布里病人群中非常普遍， 这表明这种疾病可能是了解发病机制的一个窗口， 更常见的血管疾病法布里病小鼠模型的研究 疾病首先被研究是因为它们提供了一个有用的模型， 证明了葡糖神经酰胺合酶抑制剂对于 溶酶体贮积症的治疗。最初，一系列小分子 葡糖神经酰胺合酶抑制剂被证明在 GLA敲除小鼠阻断神经酰胺三己糖苷蓄积。一个这样 抑制剂将很快进入III期临床试验。尽管GLA敲除小鼠 自发发展出任何与中观察到的血管表型相当的血管表型 Fabry病，随后的研究揭示了三种诱导实验模型 类似人类疾病的血管病变这些模型包括氧化剂 诱导血栓形成、加速动脉粥样硬化形成和血管反应性受损。一 可能将这些模型联系起来的共同机制是NO的形成受损 继发于eNOS解偶联。因此，GLA敲除小鼠不仅是有趣的， 模型，但作为一个单基因疾病代表了一个 潜在的重要模型，用于研究更常见的宏观和 微血管疾病 以下主要假设被提出作为机制联系 在这些血管异常和受损的GLA活性之间：血栓形成， 在GLA背景下观察到的促动脉粥样硬化和血管反应性异常 缺乏是由于NO生物活性降低导致内皮功能障碍的结果。 活动具体目标如下。首先，我们将确定 减少NO的生物活性的主要原因。其次，我们将确定 globo系列鞘糖脂在调节生物发生、结构和 信号传导导致eNOS活性丧失的小窝相关活性。 第三，我们将确定糖突触的组成和结构 调节VEGF和胰岛素调节内皮细胞中的eNOS活化。

Abstract Fabry disease is an X-linked lysosomal storage disorder resulting from the inherited deficiency in ¿-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.