title: Long-term RNA interference gene therapy in a dominant retinitis pigmentosa mouse model.
abstract: RNA interference (RNAi) gene silencing is a potential therapeutic strategy for dominant retinal degeneration disorders. We used self-complementary (sc) AAV2/8 vector to develop an RNAi-based gene therapy in a dominant retinal degeneration mouse model expressing bovine GCAP1(Y99C). We established an in vitro shRNA screening assay based on EGFP-tagged bovine GCAP1, and identified a shRNA that effectively silenced the bovine GCAP1 transgene with ∼80% efficiency. Subretinal injection of scAAV2/8 carrying shRNA expression cassette showed robust expression as early as 1 wk after injection. The gene silencing significantly improved photoreceptor survival, delayed disease onset, and increased visual function. Our results provide a promising strategy toward effective RNAi-based gene therapy by scAAV2/8 delivery for dominant retinal diseases.
authors: Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, UT 84132, USA.
authors: Li
authors: L
authors: Jiang
authors: Houbin
authors: H
authors: Zhang
authors: Alexander M
authors: AM
authors: Dizhoor
authors: Shannon E
authors: SE
authors: Boye
authors: William W
authors: WW
authors: Hauswirth
authors: Jeanne M
authors: JM
authors: Frederick
authors: Wolfgang
authors: W
authors: Baehr
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D004195:Disease Models, Animal; D005799:Genes, Dominant; D015316:Genetic Therapy; D051604:Guanylate Cyclase-Activating Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000628:therapy*
chemical_list: D051604:Guanylate Cyclase-Activating Proteins; C496737:Guca1a protein, mouse