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

描述(由申请人提供)： Leber先天性黑色素瘤(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几个月表现为失明或严重视力受损。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性65 kDa(RPE65)蛋白的基因突变引起的。RPE65蛋白是全反式视黄酸酯在视觉周期中转化为11-顺式视黄醇所需的维甲酸异构酶。与RPE65相关的LCA患者有严重的光感受器功能损害，如无法检测到的视网膜电信号(ERG)所示，但光感受器结构相对保存，视皮层对高强度光刺激有反应。目前还没有治疗LCA的方法，但是表达RPE65的重组腺相关病毒(RAAV)载体视网膜下注射在RPE65相关性失明的小鼠和狗模型中显示出显著的视觉功能恢复，在少数患者的初步临床试验也是令人鼓舞的。 这项研究建议的具体目的是支持1/2期临床试验，通过使用更大容量的rAAV2-CB-hRPE65来治疗由RPE65基因突变引起的Leber先天性黑色素患者的更大面积的视网膜，以补充之前报道的1期临床试验。在这项1/2期临床试验中，12名受试者(6名18岁和6名8-17岁)将接受一次450°L视网膜下注射两个剂量水平的rAAV2-CB-hRPE65。安全性将通过评估眼部和非眼部不良事件、血液学和临床化学参数以及血液中载体的存在来监测。疗效将通过评估视野、视力和视网膜电描记术来衡量。

DESCRIPTION (provided by applicant): 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 =18 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.