Translational Research for Retinal Degeneration Therapies

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DESCRIPTION (provided by applicant): A multi-investigator, multi-center research plan is proposed to develop and test gene-based retinal therapy in dog models for translation to patients with X-linked RP caused by mutations in RPGR. This uniformly severe, early onset disease accounts for ~ 8-10% RP cases in North America, 15-20% in Europe, and 25% of simplex patients. The proposal has been divided into 6 aims that will: (aim 1, 2) develop and validate vectors, promoters, knockdown constructs and replacement cDNAs for therapy of dogs having phenotypically distinct photoreceptor degenerations caused by stop or frameshift mutations in RPGR-ORF15; (aims 3, 5) establish therapy outcome measures in the models using morphologic and non-invasive functional and imaging that can be extrapolated to patients; (aim 4) perform prospective studies in RPGR-XLRP patients to determine the feasibility or facility of translating pre-clinical therapy to the clinic, and defining outcome measures to accommodate a focal therapy targeting rods and cones in the more vulnerable central retina. Six coordinated modules (M) are described, each with a distinct set of specific aims that contributes in a unique but complementary way to the 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 morphologic measures for outcome assessment. M3 (Molecular Therapeutic Development) will provide knockdown (siRNA, ribozymes) reagents, hardened wild type cDNA targets, promoters and vectors. M4 (Non-invasive Studies-Dog Models) will evaluate therapies carried out by M2 using non-invasive measures, determine functional and structural consequences of retinal remodeling, and will carry out studies that bridge the gap between animal and human (M5) research. M5 (Translational Studies in RPGR patients) will establish the relationship between the animal models and human disease expression, examine the feasibility of emerging treatments by studying retinal structure and colocalized function, design disease-specific outcome measures, and determine the natural history of the retinal degeneration. M6 (Preclinical Safety) will carry out in -05 year a GLP-based preclinical safety study of the candidate therapeutic vector as the essential first step for FDA consideration of an IND for a future Phase 1 Clinical Trial. The research studies described in this proposal represent 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 Cornell University and University of Florida.