부산대학교 도서관

Summary: 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 the ability to correct, with gene replacement, an inherent defect in bipolar cells (BCs), the excitatory interneurons of the retina. Targeting BCs with gene replacement has been difficult primarily due to the relative inaccessibility of BCs to standard AAV vectors. This approach would be useful for restoration of vision in patients with complete Congenital Stationary Night Blindness (CSNB1), where signaling through the ON BCs is eliminated due to mutations in their G-protein coupled cascade genes. For example, the majority of CSNB1 patients carry a mutation in nyctalopin ( NYX), which encodes a protein essential for proper localization of the TRPM1 cation channel required for ON BC light-evoked depolarization. As a group, CSNB1 patients have a normal electroretinogram (ERG) a-wave, indicative of photoreceptor function, but lack a b-wave due to defects in ON BC signaling. Despite retinal dysfunction, the retinas of CSNB1 patients do not degenerate. The Nyxnob mouse model of CSNB1 faithfully mimics this phenotype. Here we show that intravitreally injected, rationally designed AAV2(quadY-F+T-V) containing a novel "Ple155" promoter drives either GFP or YFP-Nyx in postnatal Nyxnob mice. In treated Nyxnob retina, robust and targeted Nyx transgene expression in ON BCs partially restored the ERG b-wave and, at the cellular level, signaling in ON BCs. Our results support the potential for gene delivery to BCs and gene replacement therapy in human CSNB1.