Phase 1/2 Trial of rAAV2-CB-hRPE65 (BB-IND 13848, 11 Sep 2009) for Leber Congenit

项目总结/摘要 莱伯先天性黑蒙是一种遗传性、遗传异质性视网膜营养不良 这通常表现为失明或严重受损的视力在出生时或在头几个月的 生活在美国的3,000名LCA患者中，大约8%至10%是由以下原因引起的： 编码视网膜色素上皮特异性65 kDa（RPE 65）蛋白的基因发生突变。RPE65 蛋白质是维A酸异构酶，其需要将全反式视黄酯转化为11-顺式-视黄醇。 介导光传导的视觉周期。患有RPE 65相关LCA的患者具有深刻的 视网膜电图（ERG）无法检测到感光器功能受损， 具有相对保存的感光器结构和完整的视觉皮层， 强度光刺激。目前没有治疗LCA的方法，但视网膜下递送 表达RPE 65的重组腺相关病毒（rAAV）载体已经证明了实质性的 RPE 65相关失明的小鼠和狗模型中的视觉功能恢复，以及 在少数病人身上进行的临床试验令人鼓舞。 本研究提案的具体目的是支持1/2期临床试验， 先前报道的1期临床试验，通过使用更大体积的rAAV2-CB-hRPE 65来治疗 Leber先天性黑蒙患者的视网膜面积更大， RPE 65基因。在这项12期临床试验中，12名受试者（6名年龄在18岁以下，6名年龄在18岁以下） 8-17年龄30岁）将在两次视网膜下注射中的一次接受rAAV2-CB-hRPE65的单次450 μ L视网膜下注射。 剂量水平。将通过评价眼部和非眼部不良事件监测安全性， 血液学和临床化学参数，以及血液中载体的存在。疗效将是 通过评估视野、视敏度和视网膜电图来测量。

Project Summary/Abstract Leber congenital amaurosis (LCA) is an inherited, genetically heterogeneous form of retinal dystrophy that usually presents as blindness or severely impaired vision at birth or during the first few months of life. Among the 3,000 patients with LCA in the United States, approximately 8 to 10% are caused by mutations in a gene encoding a retinal pigment epithelium-specific 65 kDa (RPE65) protein. RPE65 protein is the retinoid isomerase required for conversion of all-trans-retinyl ester to 11-cis-retinol in the visual cycle that mediates phototransduction. Patients with RPE65-associated LCA have profound impairment of photoreceptor function as indicated by a nondetectable electroretinogram (ERG) but with relatively preserved photoreceptor structure and an intact visual cortex that is responsive to high intensity light stimulation. No treatment for LCA is currently available, but subretinal delivery of recombinant adeno-associated virus (rAAV) vectors expressing RPE65 has demonstrated substantial restoration of visual function in mouse and dog models of RPE65-associated blindness, and initial clinical trials in small numbers of patients has been encouraging. The specific aim of this research proposal is to support a Phase 1/2 clinical trial that will complement the previously reported Phase 1 clinical trials, by using a larger volume of rAAV2-CB-hRPE65 to treat a larger area of the retina in patients with Leber congenital amaurosis caused by mutations in the RPE65 gene. In this Phase 1/2 clinical trial, 12 subjects (6 who are e18 years of age and 6 who are 8-17 years of age) will receive a single 450 ¿L subretinal injection of rAAV2-CB-hRPE65 at one of two dosage levels. Safety will be monitored by evaluation of ocular and non-ocular adverse events, hematology and clinical chemistry parameters, and presence of the vector in blood. Efficacy will be measured by evaluation of visual fields, visual acuity and electroretinography.