(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.
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