Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration

摘要: Retinitis pigmentosa (RP) is a group of inherited neurological disorders characterized by rod photoreceptor cell death, followed secondary cone death leading to progressive blindness. Currently, there are no viable treatment options for RP. Due incomplete knowledge the molecular signaling pathways associated with RP pathogenesis, designing therapeutic strategies remains challenge. In particular, preventing loss key goal in potential therapies. this study, we identified main drivers and transgenic S334ter rhodopsin rat model, tested efficacy specific inhibitors on retinal function, compared effect combining drugs target multiple P23H models. The primary driver early model was caspase-dependent process, whereas occurred though RIP3-dependent necroptosis. comparison, via necroptotic signaling, through inflammasome activation. Combination therapy four worked better than individual but not model. These differences imply that modalities need be tailored each genotype. Taken together, our data demonstrate rationally designed genotype-specific drug combinations will an important requisite effectively more importantly survival.