Gene Therapy for Leber Congenital Amaurosis

莱伯先天性黑蒙的基因治疗

• 批准号: 6804676
• 负责人: WILLIAM W HAUSWIRTH
• 金额: $ 271.85万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804676
• 关键词: Lentivirus; adeno associated virus group; autosomal recessive trait; biological models; biotechnology; blindness; clinical research; clinical trial phase I; congenital vision disorder; cooperative study; dogs; drug screening /evaluation; gene delivery system; gene therapy; genetically modified animals; human subject; human therapy evaluation; laboratory mouse; longitudinal animal study; retina degeneration; retinal pigment epithelium; technology /technique development; transfection /expression vector; vision tests

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.

描述：（申请人的摘要）多研究者、多中心 提出了开发基于病毒载体的基因疗法的研究/临床计划 针对 RPE65 Leber 先天性黑蒙 (LCA)，以完成临床前安全性 测试向 FDA 提交的研究性新药 (IND) 并 开始I/II期临床试验。描述了七个协调模块， 每个都有一套独特的具体目标，这些目标有助于形成独特和 实现治疗目标的补充方式。模块 1，RPE65 矢量 生产将改善 LCA 临床试验的 AAV 载体生产 将为其他模块提供研究和 GMP 级载体。模块 2，RPE65 载体改进将提高 Rpe65 的体内效率和特异性 通过启动子和载体在动物模型中的 RPE 细胞中进行基因递送/表达 修改。模块 3，RPE65 小鼠研究将优化治疗 病毒（AAV 和慢病毒）载体传递的 RPE65 基因的影响并评估 Rpe65 敲除小鼠中的任何毒性作用。第 4 单元，RPE65 犬类研究 将评估载体给药方案对 RPE65 治疗结果的影响 RPE65 突变狗的基因增强。模块 5，RPE65 LCA 人类研究 将鉴定适合进入 I/II 期基因的 RPE65 LCA 患者 治疗试验并制定标准化试验结果衡量标准。模块 6，RPE65 LCA临床试验，有两个方面：6A、临床前测试和IND 发展，将确定对人体的潜在毒性和范围 在动物模型中视网膜下 AAV-RPE65 的有效剂量并制定 FDA 批准 613 的临床方案； 6B，IM阶段试验将评估安全性 AAVRPE65基因替代疗法治疗RPE65 LCA的初步疗效-The 基础科学模块 1、2、3 和 4。以及临床筛查模块 5 还开发了可用于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。这 佛罗里达大学领导了与佛罗里达大学的这项合作 宾夕法尼亚大学和康奈尔大学。爱荷华大学和华盛顿大学 是分包合作者。