Retinal degeneration diseases are a common cause of untreatable blindness worldwide, affecting the lives of millions. The only FDA-approved treatment for these disorders is gene therapy for specific RPE65 mutations that cause Leber?s congenital amaurosis and retinitis pigmentosa. One major limitation to the development of effective therapies is the use of model systems that poorly replicate the human condition. Particularly for cone disorders, studies that use model systems with a rod-dominant retina and no true macula have substantive limitations. We propose to develop a series of novel and spontaneous animal models of human inherited retinal diseases. In preliminary analyses, we have identified a new spontaneous model directly relevant to human retinal disease. Genetic testing identified four individuals homozygous for a naturally occurring damaging mutation in the PDE6C gene, which has previously been associated with cone dystrophy in humans. Scotopic and photopic full-field electroretinograms performed on animals homozygous for the PDE6C mutation demonstrated a relatively normal rod response but no cone response whatsoever. A subtle but characteristic retinopathy was identified using fundus photography, blue autofluorescence, and fluorescein angiography with concurrent foveal thinning using spectral-domain optical coherence tomography. Our genetic survey also identified individuals with mutations in 7 other human retinal disease genes that are predicted to severely damage gene or protein function, pointing to possible additional new models. To develop the new model of PDE6C cone dystrophy, and make this and other new models available to the vision research community, we propose four Specific Aims: 1) to identify and genetically characterize new animal models of human retinal disease via DNA sequencing, 2) to perform complete ophthalmic phenotyping of the new models of retinal disease, 3) to breed a colony of animals with PDE6C cone dystrophy and 4) to compare cell-based and gene replacement therapies in these subjects with PDE6C cone dystrophy mutations. Successful completion of this work will produce a well-characterized new animal model of inherited cone dystrophy with significantly greater similarity to human disease than existing models, thus providing substantially better translation to subsequent human trials. In addition, affected animals will be made available to the wider vision research community, and other new models with similar potential will be identified.
Retinal degeneration is a major cause of visual impairment and blindness in humans, but there are few effective treatments available to the many patients in need. The goal of this project is to advance the pace and efficiency of research regarding treatments for retinal degeneration disease by developing novel spontaneous (not induced) models of human retinal disease. By developing new and better model systems, and making those models available to the wider vision research community, this project will speed the development and efficacy testing of innovative therapies, including cell and gene therapy, that will reduce the morbidity caused by retinal degeneration diseases in humans.
