Mutations responsible for blinding human retinal degenerative diseases have been identified in a least 132 separate genes, most of which are expressed primarily in photoreceptor cells of the neural retina. These include hundreds of mutations in at least 132 different genes, over 60% of which have been cloned (see A number of animal models for hereditary retinal degeneration now exist, including spontaneous mutants and animals genetically engineered for various mutations that have been identified in humans with retinal degeneration. In particular, at least two mammalian animal models exist for PDEbeta defects causing retinitis pigmentosa (the rd1 mouse and the rcd1 dog) and one model exists for Stargardt macular degeneration (the abcr-/- mouse). Recent findings from our group suggest that it may now be possible to treat hereditary retinal degenerations on a long-term if not permanent basis with genetic therapy: (1) Recombinant replication-deficient adeno-associated viruses (AAVs) can be used to transduce terminally differentiated photoreceptor (and retinal pigment epithelium) cells efficiently in vivo with no apparent toxicity. High levels of expression persist for months and years. For therapy for lack-of-function disease, AAV-mediated transduction is expected to be permanent if the photoreceptors survive the time period necessary to obtain high levels of transgene expression with this vector. (2) AAV2-mediated therapy in the dog model of Leber Congenital Amaurosis provided these dogs, who had been born blind, with vision. It may thus be possible to use similar strategies to treat retinal degeneration originating in the neural retina. We propose to optimize AAV-mediated delivery of PDEbeta to neural retinas of murine and canine animal models of RP. We also propose to use AAV to treat an animal model of another primary photoreceptor disease - Stargardt macular degeneration. The research proposed here aims to determine whether AAV-mediated introduction of the appropriate wild-type transgene (PDEbeta or abcr) can reverse or slow the degeneration in the relevant animal models. Therapeutic and other effects of wild-type PDEbeta and abcr protein will be assessed qualitatively and quantitatively after AAV-mediated gene transfer. The ability to rescue photoreceptors in the PDEbeta or abcr -based animal models could ultimately pave the way for genetic therapy as a treatment for blinding retinal diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISC (01))
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Dudley, Peter A
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University of Pennsylvania
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Bennett, Jean (2017) Taking Stock of Retinal Gene Therapy: Looking Back and Moving Forward. Mol Ther 25:1076-1094
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