FABRY DISEASE 025

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。α-半乳糖苷酶A(GAL)是一种溶酶体水解酶，负责球三糖神经酰胺(GL-3)的代谢，GL-3是该酶的主要糖磷脂底物。在Fabry病中，遗传的GAL缺乏会导致GL-3在心脏、肾脏、肝脏、皮肤和肠道中广泛沉积，在较小程度上还会导致其他含有α-半乳糖苷的糖脂沉积。Fabry病的主要临床症状和体征包括皮肤损害、良性角膜和晶状体混浊、剧烈的肢端疼痛、感觉异常、自主神经功能障碍、心脏病和肾功能衰竭。在微血管中进行性的糖脂沉积导致靶器官衰竭，导致在生命的第三到五十年死亡。由于X染色体携带GAL基因，大多数受影响的患者是半合子男性，尽管一些杂合子女性也可能因裂解(一条X染色体的随机失活)而受到影响。法布里病的共同表现是严重的内皮功能障碍，影响血管的结构、血管反应性和完整性。最终，内皮血管床的失效会导致无数的病理生理事件，导致中枢、外周和自主神经系统疾病、心脏病和肾脏疾病。最近，治疗Fabry病的酶替代疗法已被批准在包括欧盟、澳大利亚和美国(US)在内的几个全球市场上市。Genzyme公司制造了一种重组形式的人α-半乳糖苷酶A(r-hGAL；Fradzyme)，用于为Fabry病患者提供替代酶。1/2期单中心、开放标签、剂量发现、安全性和药代动力学研究已经完成。这项研究提供了储存的鞘糖脂从靶组织中清除的药效学证据，表明生理改善和潜在的临床益处。一项多国家、随机、双盲、安慰剂对照的关键阶段3期研究也已完成。与安慰剂相比，最常见的不良事件是与输液相关的(僵硬和发烧)。此外，包括临床化学、血液学和尿液分析在内的实验室研究没有表明使用Fradzyme治疗有任何直接毒性作用。两项试验都表明，将储存在血管内皮细胞床上的鞘糖脂降低到正常或接近正常水平，作为替代终点，可能预测Fabry患者的临床益处。研究人员手册和/或产品标签中提供了有关Fradzyme的非临床和临床安全性和有效性的详细信息。这项开放标签试验的目的是证明和证实法布里病患者应用法布拉酶的安全性和有效性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alpha-galactosidase A (GAL) is a lysosomal hydrolase enzyme responsible for the metabolism of globotriaosylceramide (GL-3), the enzyme's major glycosphingolipid substrate. In Fabry disease, an inherited deficiency of GAL leads to widespread deposition of GL-3, and to a lesser extent other Alpha -galactoside-containing glycolipids, in the heart, kidney, liver, skin, and intestines. The major clinical signs and symptoms of Fabry disease include skin lesions, benign corneal and lenticular opacities, excruciating acral pain, paresthesias, autonomic dysfunction, cardiac disease, and renal failure. Progressive glycolipid deposition in the microvasculature leads to failure of target organs resulting in death in the third to fifth decades of life. Because the X-chromosome carries the GAL gene, most affected patients are hemizygous males, although some heterozygous females can also be affected due to lyonization (random inactivation of one X-chromosome). The common element in the manifestations of Fabry disease is severe endothelial dysfunction affecting the structure, vasoreactivity and integrity of blood vessels. Ultimately, failure of endothelial vascular beds results in the myriad pathophysiologic events leading to central, peripheral and autonomic nervous system disease, cardiac disease and renal disease. Recently, enzyme replacement therapy for Fabry disease has been approved to market in several global markets including the European Union, Australia, and the United States (US). Genzyme Corporation has manufactured a recombinant form of human Alpha-galactosidase A (r-hGAL; Fabrazyme) to provide replacement enzyme to patients with Fabry disease. A Phase 1/2 single center, open label, dose finding, safety and pharmacokinetic study has been completed. This study provided evidence of pharmacodynamic clearance of stored glycosphingolipid from target tissues, suggesting physiologic improvement and potential for clinical benefit. A multi-national, randomized, double blind placebo controlled pivotal Phase 3 study has also been completed. The most frequent adverse events compared to placebo were infusion related (rigors and fever). In addition, laboratory studies including clinical chemistry, hematology, and urinalysis did not show that treatment with Fabrazyme had any direct toxic effects. Both trials demonstrated pharmacodynamic reduction to normal or near-normal levels of stored glycosphingolipid from vascular endothelial beds as surrogate endpoints likely to predict clinical benefit in Fabry patients. Detailed information regarding the non-clinical and clinical safety and efficacy of Fabrazyme is provided in the Investigator Brochure and/ or product labeling. This open-label trial is designed to demonstrate and confirm the safety and effectiveness of Fabrazyme in patients with Fabry dis