Inherited retinal diseases (IRDs) such as retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy, and Best macular dystrophy are devastating blinding diseases in people. While mutations in nearly 270 genes have been associated with different forms of IRDs to date, characterization of disease mechanisms and identification of therapeutic targets for many of these IRDs are yet to be developed. Encouraging clinical successes with gene replacement therapy have emerged in recent years for several forms of IRD in man, and some of these treatments have resulted from proof of principle studies carried out in dog models by our research group. At the Retinal Disease Study Facility of the University of Pennsylvania, we have an established research capability and expertise that has allowed us to mechanistically assess over 20 canine strains and their crosses, each of which represent different forms of naturally-occurring IRDs. Using a subset of these canine models, we aim to better understand the molecular basis and pathogenic mechanisms of these unique IRDs, and evaluate new therapies to prevent or ameliorate disease. Thus renewal of the proposed program will allow continued advances in translational studies using canine models of IRDs, providing a sound basis for future development of new and effective therapies for human retinal degenerative diseases. At our centralized resource facility, we will breed and maintain specific canine IRD strains with rigorously characterized phenotypes/genotypes. Investigators will be provided with mutant and age-matched control dogs either for independent or collaborative studies.
The aim of these studies is to understand the molecular mechanisms involved in IRDs, and develop new therapies that can be evaluated on a short- or long-term basis. This centralized resource will also be used by multiple investigators to accomplish the research goals of their own NIH-funded grants. Lastly, hypothesis-driven studies by the PIs and collaborators will be aimed at characterizing new patient-relevant IRD models, studying their underlying cellular/molecular mechanisms, examining the role of inflammation and microglia/macrophages in IRDs for the identification of optimal therapeutic targets, optimizing targeting of different retinal cell types such as ON-bipolar cells, and testing the effect of a new protease in facilitating intravitreal AAV therapies. Our principal hypothesis is that the collaborative research using canine models from a centralized, well- maintained resource facility, supported by a team of investigators with expertise in both clinical ophthalmology and molecular/cell biology, will lead to critical proof-of-principle studies directed at developing safe and effective new therapies for IRDs in patients. The proposed program and studies are designed to fully address this hypothesis.
Inherited retinal diseases that lead to devastating blinding conditions were previously considered incurable, but a handful of them can now be treated with emerging new gene therapy options. However, before potential therapies can be made available for patients, it is critical that they are tested for effectiveness and evaluated for safety in appropriate clinically-relevant model systems. The research proposal aims to understand the mechanisms of genetic mutations causing retinal diseases, and to establish preclinical proof-of-principle by developing and testing new therapies that prevent or delay the retinal degeneration that leads to blindness.
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