A multi-investigator, multi-center research plan is proposed to finalize the development of gene-based retinal therapy in dog models of X-linked RP caused by mutations in RPGR prior to use in human patients. This uniformly severe, early onset human disease accounts for ~ 8-10% RP cases in North America, 15-20% in Europe, and 25% of simplex patients. The application builds on the success achieved during the current funding period which developed an AAV5-based viral vector that, together with the human IRBP promoter and human full-length RPGR cDNA, prevents the retina from degenerating in the 'slow'disease model (XLPRA1), or arrests the degeneration and maintains the photoreceptors at normal integrity in the 'fast'disease model (XLPRA2). This vector now serves as the benchmark therapeutic reagent for assessing treatment paradigms, and testing a novel therapeutic approach via the intravitreal route of delivery. The application will evaluate gene therapy in dogs having phenotypically distinct photoreceptor degenerations caused by stop or frameshift mutations in RPGRORF15, and is divided into 3 aims that will: 1-assess the long term efficacy of treatment and determine the dose-response range to establish efficacy vs toxicity dose~ 2- facilitate translational studies by targeting treatment to patient-relevant disease stage to assess treatment outcomes using criteria established during the current funding period~ 3- carry out comparative efficacy studies on modified vectors delivered via the intravitreal route that avoid secondary surgical trauma in compromised diseased photoreceptors. Four coordinated modules (M) are described that take advantage of the special expertise of each group to create a complementary and focused approach to the proposed translational studies. M1 (Large Animal experimental) will produce the dog models, and provide infrastructure resources for this work~ M2 (Large Animal Therapy) will carry out therapy studies in the canine models and develop ex vivo morphologic measures for outcome assessment~ M3 (Non-invasive Studies-Dog Models) will establish functional and structural disease features, and evaluate success of therapies using non-invasive outcome measures chosen appropriate for RPGR disease, and correlate the results with ex vivo morphologic studies~ M4 (Molecular Therapeutic Development) will provide therapeutic vectors for both subretinal and intravitreal delivery. The research studies described in this application represents a continuation of a longstanding collaboration between the module scientists that already has brought retinal gene therapy for RPE65-LCA patients to a Phase I clinical trial. The University of Pennsylvania leads this collaboration with the University of Florida.
X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is among the most severe and common causes of inherited retinal blindness in man. To finalize the development of gene therapy for use in human patients, we will exploit viral vectors already proven effective in preventing or arresting disease in two canine models, and optimize treatments at disease stages comparable to human patients using either subretinal or intravitreal delivery routes.
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