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：（申请人摘要）多中心 提出了研究/临床计划来开发基于病毒的基因治疗 RPE65 Leber先天性症（LCA），以完成临床前安全 测试对FDA提交的调查新药（IND）的测试 开始I/II期临床测试。描述了七个协调模块， 每个都有一组独特的特定目标，以独特的和 朝着治疗目标的免费方式。模块1，RPE65矢量 生产将改善LCA临床试验的AAV载体生产和 将为其他模块提供研究和GMP等级向量。模块2，RPE65 向量改进将提高RPE65的体内效率和特异性 动物模型中RPE细胞中的基因输送/表达通过启动子和载体 修改。模块3，RPE65小鼠研究将优化治疗性 病毒（AAV和慢病毒）载体分割的RPE65基因的影响并评估 RPE65中的任何有毒作用都将小鼠击倒。模块4，RPE65犬研究 将根据RPE65的治疗结果评估媒介管理方案 RPE65突变犬中的基因增强。模块5，RPE65 LCA人类研究 将识别适合进入I/II期基因的RPE65 LCA患者 治疗试验并制定标准化试验结果指标。模块6，RPE65 LCA临床试验有两个方面：6A，临床前测试和IND 发展将确定人类毒性的潜力和 动物模型中有效剂量的视网膜下AAV-RPE65并开发FDA 批准的613临床方案； 6B，IM试验将评估安全性 AAVRPE65基因替代疗法RPE65 LCA的初步功效 - 基础科学模块1、2、3和4。以及临床筛查模块5 还开发出临床前毒性研究的信息，模块 这些模块在最初三年生成的6a-数据将有助于指导 计划在3/4年开始的模块6B的临床试验设计。这 佛罗里达大学领导与大学的合作 宾夕法尼亚州和康奈尔大学。爱荷华州和华盛顿大学 是分包合作者。