Gene Therapy for Leber Congenital Amaurosis

描述：(应聘者？S摘要)多调查员、多中心 提出研究/临床计划，以发展基于病毒载体的基因治疗 对于RPE65 Leber先天性黑色素(LCA)，完全临床前安全 检测提交给FDA的研究用新药(IND)和 开始I/II期临床试验。描述了七个协调模块， 每个人都有一套不同的具体目标，这些目标有助于 朝着治疗目标的赠与之路。模块1，RPE65向量 生产将改善用于LCA临床试验的AAV载体的生产，并 将为其他模块提供研究和GMP等级矢量。模块2，RPE65 载体的改进将提高RPE65的体内效率和特异性 启动子和载体在动物模型RPE细胞中的基因传递/表达 修改。模块3，RPE65小鼠研究将优化治疗 病毒(AAV和慢病毒)载体携带RPE65基因的效果及评价 RPE65基因敲除小鼠的任何毒性作用。单元4，RPE65犬科研究 将评估载体给药方案对RPE65的治疗效果 RPE65突变犬的基因扩增。单元5，RPE65 LCA人体研究 将确定适合进入I/II期基因的RPE65 LCA患者 治疗试验和制定标准化的试验结果衡量标准。模块6，RPE65 LCA临床试验，有两个方面：6A，临床前试验和IND 发展，将决定对人类的潜在毒性和范围 视网膜下注射AAV-RPE65的有效剂量及FDA的建立 批准的613；6B期IM试验的临床方案将评估安全性 AAVRPE65基因替代疗法治疗RPE65 LCA的初步疗效 基础科学单元1、2、3、4和临床筛选单元5 还开发提供给临床前毒性研究的信息，模块 6A-这些模块在前3年生成的数据将有助于指导 模块6B的临床试验设计，计划于3/4年开始。 佛罗里达大学领导着这项与加州大学 宾夕法尼亚大学和康奈尔大学。爱荷华州大学和华盛顿大学 是分包合作者。

DESCRIPTION: (Applicant?s Abstract) A multi-investigator, multi-center research/clinical plan is proposed to develop a viral vector-based gene therapy for RPE65 Leber congenital amaurosis (LCA), to complete preclinical safety testing for an Investigational New Drug (IND) submission to the FDA and to begin Phase I/II clinical testing. Seven coordinated modules are described, each with a distinct set of specific aims that contributes in a unique and complimentary way towards the therapeutic goal. Module 1, RPE65 Vector Production will improve AAV vector production for the LCA clinical trial and will provide research and GMP grade vectors for other modules. Module 2, RPE65 Vector improvement will enhance the in vivo efficiency and specificity of Rpe65 gene delivery/expression in RPE cells in animal models by promoter and vector modifications. Module3, RPE65 Mouse Studies will optimize the therapeutic effect of viral (AAV and Lentivirus) vector-delivered RPE65 genes and evaluate any toxic effects in the Rpe65 knock out mouse. Module 4, RPE65 Canine Studies will evaluate vector administration options on the therapeutic outcome of RPE65 gene augmentation in the RPE65 mutant dog. Module 5, RPE65 LCA Human Studies will identify RPE65 LCA patients suitable for entry into a Phase I/II gene therapy trial and develop standardized trial outcome measures. Module 6, RPE65 LCA Clinical Trial, has two aspects: 6A, Pre-clinical Testing and IND Development, will determine the potential for human toxicity and the range of efficacious doses of subretinal AAV-RPE65 in animal models and develop an FDA approved clinical protocol for 613; 6B, Phase IM Trial will evaluate the safety and preliminary efficacy of AAVRPE65 gene replacement therapy for RPE65 LCA-The basic science Modules 1, 2, 3, and 4. and the clinical screening Module 5 also develop information that feeds into the preclinical toxicity study, Module 6A- Data generated in the first 3 years by these modules will help guide the clinical trial design of Module 6B that is scheduled to begin in year 3/4. The University of Florida leads this collaboration with the University of Pennsylvania and Cornell University. The Universities of Iowa and Washington are subcontracting collaborators.