FABRY DISEASE 025

法布里病 025

• 批准号: 7377349
• 负责人: ROBERT A GREENSTEIN
• 金额: $ 0.14万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377349
• 关键词: FABRY; DISEASE; 025

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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。α-半乳糖苷酶A（GAL）是一种溶酶体水解酶，负责神经酰胺三己糖苷（GL-3）（该酶的主要鞘糖脂底物）的代谢。在法布里病中，GAL的遗传性缺乏导致GL-3广泛沉积，并在较小程度上导致其他含α-半乳糖苷的糖脂在心脏、肾脏、肝脏、皮肤和肠道中广泛沉积。法布里病的主要临床体征和症状包括皮肤病变、良性角膜和晶状体混浊、极度疼痛、感觉异常、自主神经功能障碍、心脏病和肾衰竭。 微血管系统中进行性糖脂沉积导致靶器官衰竭，导致生命的第三至第五个十年死亡。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Lyonization（一条X染色体的随机失活）而受到影响。法布里病临床表现的共同点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，内皮血管床的衰竭导致无数病理生理事件，导致中枢、外周和自主神经系统疾病、心脏病和肾病。 最近，法布里病的酶替代疗法已在包括欧盟、澳大利亚和美国（US）在内的多个全球市场获批上市。Genzyme Corporation生产了重组形式的人α-半乳糖苷酶A（r-hGAL; Fabrazyme），为法布里病患者提供替代酶。已完成一项I/II期单中心、开放标签、剂量探索、安全性和药代动力学研究。本研究提供了从靶组织中清除储存鞘糖脂的药效学证据，表明生理改善和潜在临床获益。一项多国、随机、双盲、安慰剂对照的关键III期研究也已完成。与安慰剂相比，最常见的不良事件为输注相关（寒战和发热）。此外，包括临床生化、血液学和尿分析在内的实验室研究未显示Fabrazyme治疗有任何直接毒性作用。两项试验均证明，作为替代终点，血管内皮床储存的鞘糖脂的药效学降低至正常或接近正常水平，可能预测法布里病患者的临床获益。关于Fabrazyme的非临床和临床安全性和疗效的详细信息见研究者手册和/或产品标签。 这项开放标签试验旨在证明和确认Fabrazyme在法布里病患者中的安全性和有效性。