Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness

摘要: Adeno-associated virus (AAV) effectively targets therapeutic genes to photoreceptors, pigment epithelia, Muller glia and ganglion cells of the retina. To date, no one has shown ability correct, with gene replacement, an inherent defect in bipolar (BCs), excitatory interneurons Targeting BCs replacement been difficult primarily due relative inaccessibility standard AAV vectors. This approach would be useful for restoration vision patients complete congenital stationary night blindness (CSNB1), where signaling through ON is eliminated mutations their G-protein-coupled cascade genes. For example, majority CSNB1 carry a mutation nyctalopin (NYX), which encodes protein essential proper localization TRPM1 cation channel required BC light-evoked depolarization. As group, have normal electroretinogram (ERG) a-wave, indicative photoreceptor function, but lack b-wave defects signaling. Despite retinal dysfunction, retinas do not degenerate. The Nyx(nob) mouse model faithfully mimics this phenotype. Here, we show that intravitreally injected, rationally designed AAV2(quadY-F+T-V) containing novel 'Ple155' promoter drives either GFP or YFP_Nyx postnatal mice. In treated retina, robust targeted Nyx transgene expression partially restored ERG and, at cellular level, BCs. Our results support potential delivery therapy human CSNB1.