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

项目摘要/摘要 Leber先天性黑色素沉着症(LCA)是一种遗传性、遗传异质性的视网膜营养不良 通常在出生时或出生后的头几个月表现为失明或视力严重受损 生活。在美国3000名LCA患者中，约8%至10%是由 编码视网膜色素上皮特异的65 kDa(RPE65)蛋白的基因突变。RPE65 蛋白质是全反式视黄酸酯转化为11-顺式视黄醇所必需的类维A酸异构酶。 调节光传导的视觉循环。与RPE65相关的LCA患者有深刻的 不可检测的视网膜电信号(ERG)表明光感受器功能受损，但 具有相对保存的光感受器结构和对高强度反应的完整视觉皮质 强度光刺激。目前还没有治疗LCA的方法，但视网膜下注射 表达RPE65的重组腺相关病毒载体已证实 RPE65致盲小鼠和狗模型的视功能恢复 在少数患者中进行的临床试验令人鼓舞。 这项研究提案的具体目标是支持1/2期临床试验，该试验将补充 之前报道的1期临床试验，通过使用更大体积的rAAV2-CB-hRPE65来治疗 基因突变导致Leber先天性黑色素症患者视网膜面积较大 RPE65基因。在这项1/2期临床试验中，12名受试者(6名为E18岁，6名为 8-17岁)将接受L视网膜下注射rAAV2-CB-hRPE65 剂量水平。安全性将通过评估眼部和非眼部不良事件进行监测， 血液学和临床化学参数，以及血液中是否存在载体。功效将是 通过评估视野、视力和视网膜电流图进行测量。

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.