Models of Hereditary Retinal Degenerations

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DESCRIPTION (provided by applicant): This application aims to hasten development of specific, safe, and effective therapies for human hereditary retinal degenerations by initiating, conducting and making resources available for studies of well characterized canine strains affected with similar diseases. It has 3 broad aspects: 1) to identify, develop, maintain, and produce canine mutant models for human retinal degenerations; the need for these animals in research and the importance of maintaining them in a centralized facility is addressed; 2) to initiate and continue studies to clone the genes for these diseases, investigate the cellular and molecular biology of these diseases, and develop and test methods for therapeutic intervention; 3) to institute and conduct therapeutic trials in collaborations with independent investigators from either academic or industrial organizations. Each such study is peer reviewed, separately, as part of the collaborative investigators' research protocols. Research investigations will focus on studies appropriate to each strain. Seven of these well characterized mutant canine strains represent identified mutations in 5 different genes (2 allelic achromatopsia models: cd1, cd2; rod-cone dysplasia type 1: rcd1; a canine rpe65- model of Leber Congenital Amaurosis; a T4R Opsin mutant; and 2 allelic RPGRORF15 mutants: XLPRA1 and XLPRA2). Mapping, positional cloning, and candidate gene studies in progress will continue to be undertaken to identify the responsible genes and mutations in the remaining models (early retinal degeneration: erd; progressive rod-cone degeneration: prcd; rod-cone dysplasia type 2: rcd2; and dogs affected with unique cone rod dystrophies). Specific canine strains transmitting each of these disorders, together with appropriate nonaffected control dogs, are currently bred, maintained and studied in this project. They and their progeny will be studied in collaborative research investigations, either directly or by collection, processing and distribution of requested tissues. Collaborations to effectively utilize these mutants will be initiated by the Principal Investigator interacting with independently funded investigators, to develop, implement and conduct specific protocols for optimal utilization of these mutants. Specific collaborative research includes programs to: identify, clone, and characterize the gene mutations for erd; prcd; and rcd2; determine and compare the role of programmed cell death genes in each of the mutant strains; further develop therapies for hereditary retinal degenerations including vector mediated gene transfer into canine photoreceptors; retinoid isomer therapy; modulation of the photoreceptor apoptotic pathway; and application of a visual-prosthetic silicon retinal implant.