Project Summary/Abstract 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 animal models that poorly replicate the human condition. Particularly for cone disorders, studies that use animals with a rod-dominant retina and no true macula have substantive limitations. By contrast, the cone-rich macula of nonhuman primates (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders, that are more predictive of human conditions are necessary to more efficiently advance new therapies. We propose to develop a series of novel and spontaneous NHP models of human inherited retinal diseases. Behavioral observations of rhesus macaques (Macaca mulatta) at the California National Primate Research Center identified a series of macaques that displayed apparent visual impairment. Genetic testing showed that four animals are homozygous for a damaging mutation in the PDE6C gene, which has previously been associated with cone dystrophy in humans. Scotopic and photopic full-field electroretinograms performed on macaques homozygous for the PDE6C mutation demonstrated a relatively normal rod response but no cone response whatsoever. A subtle but characteristic bullseye maculopathy was identified using fundus photography, blue autofluorescence, and fluorescein angiography with concurrent foveal thinning using spectral-domain optical coherence tomography. Our genetic survey of this population also identified macaques 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 PDE6C primate model of cone dystrophy, and make this and other new NHP models available to the vision research community, we propose four Specific Aims: 1) to identify and genetically characterize new NHP models of human retinal disease via DNA sequencing, 2) to perform complete ophthalmic phenotyping of NHP models of retinal disease, 3) to breed a colony of NHPs with PDE6C cone dystrophy and 4) to compare cell-based and gene replacement therapies in macaques 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.