A Novel Model of Photoreceptor Degeneration

Oregon Health & Science University, Portland OR

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Abstract

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. In the last year we found a family of rhesus monkeys with Bardet-Biedl syndrome, a disorder resulting in severe retinal degeneration combined with kidney disease. 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 define the time course of the degeneration so that it can be used for future efforts to develop treatments. The specific aims of this proposal are: 1. To generate and cryopreserve rhesus embryos confirmed to have the BBS7 mutation. We will use eggs and sperm collected from BBS7 carriers to produce embryos by in vitro fertilization, and use genetic sequencing of embryo biopsies to select embryos with two copies of the disease-causing mutation. 2. To produce live affected infants by transfer of selected blastocysts to surrogate mothers, using methods optimized for decades by the ONPRC Assisted Reproductive Technologies Core. 3. To characterize the time course of the disease in affected infants from birth by comprehensive retinal imaging and functional assessments like those used in human patients. 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 characterize a primate model of an inherited retinal degeneration so that, in the future, we can use these animals to test cell replacement approaches to therapy for this entire class of blinding disorders. Our goal is to preserve vision in these animals and in human patients with this and similar blinding diseases.