Nonhuman Primate Model of Inherited Photoreceptor Degeneration

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PROJECT SUMMARY Blindness can be caused by many genetic mutations that lead to degeneration of the retina, but most of these diseases have no treatments. The development of safe and effective treatments critically depends on the ability to test them in appropriate animal models before using them in human patients. Because nonhuman primates are the only animals with retinal structure like humans, including the macula that underlies central vision, they have the potential to provide the most accurate and informative models of blinding diseases. Indeed, the lack of such models has been identified as a major impediment to the rapid translation of promising therapies to clinical use for preventing and treating blindness. We have spent many years screening the large macaque colony at the Oregon National Primate Research Center for naturally-occurring retinal diseases. We recently discovered a family of rhesus monkeys with Bardet-Biedl syndrome, an inherited disease resulting in severe retinal degeneration combined with kidney disease, which closely resembles the human form of this disorder. We identified the cause as a mutation in the BBS7 gene, genotyped a pedigree including at least 50 carriers, and examined the nature of the retinal degeneration by histopathology. We now propose to propagate this model, and use it to test a novel gene therapy with high potential to preserve and restore sight in this and similar diseases in human patients. The specific aims of this proposal are: 1. To breed animals with Bardet-Biedl syndrome and determine the characteristics and time course of the disease. 2. To deliver a gene therapy to animals with this disease and evaluate its ability to preserve or restore central vision. This spontaneously-occurring monkey disorder closely mirrors Bardet-Biedl syndrome as seen in human patients. In addition to providing a model of this specific genetic disease, it also provides a model for the large family of similar retinal degenerations called retinitis pigmentosa that together are a major inherited cause of blindness. This discovery provides us with a unique opportunity to propagate and characterize a primate model of an inherited retinal degeneration and to use these animals to test gene therapy approaches to therapy for this entire class of blinding disorders. Our goal is to develop a method to preserve and restore vision in human patients with this and many other blinding diseases.