Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilize a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing variables that complicate answering this question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restore retinal output to near wild-type levels. Late treatment retinas exhibit continued, albeit slowed, loss of sensitivity and signal fidelity among retinal ganglion cells, as well as persistent gliosis. We conclude that gene replacement therapies delivered after 50% rod loss are unlikely to restore visual function to normal. This is critical information for administering gene therapies to rescue vision.

视网膜色素变性是一种遗传性光感受器变性，以视杆细胞丢失开始，然后是视锥细胞丢失。这种细胞损失会大大降低视力，大多数患者在法律上失明。基因疗法正在开发中，但尚不清楚视网膜功能如何取决于干预时间。为了揭示这种依赖性，我们利用了能够进行人工遗传拯救的视网膜色素变性小鼠模型。该模型通过消除使回答这个问题复杂化的变量，实现了最佳情况基因治疗的基准。在 25% 、 50% 和 70% 的杆损失 （分别为早期、中期和晚期） 进行完全基因拯救。早期和中期治疗可将视网膜输出恢复到接近野生型的水平。晚期治疗视网膜表现出视网膜神经节细胞中敏感性和信号保真度的持续丧失，尽管速度减慢，以及持续的神经胶质增生。我们得出结论，在视杆损失 50% 后提供的基因替代疗法不太可能使视觉功能恢复正常。这是进行基因疗法以挽救视力的关键信息。