Scalabrino Miranda L, Thapa Mishek, Wang Tian, Sampath Alapakkam P, Chen Jeannie, Field Greg D
Stein Eye Institute, Department of Ophthalmology, University of California, Los Angeles CA.
Department of Neurobiology, Duke University School of Medicine, Durham NC.
bioRxiv. 2023 Apr 8:2023.04.07.536035. doi: 10.1101/2023.04.07.536035.
Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss and eventual blindness. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilized a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing the variables that complicate the ability to answer this vital question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restored retinal function to near wild-type levels, specifically the sensitivity and signal fidelity of retinal ganglion cells (RGCs), the 'output' neurons of the retina. However, some anatomical defects persisted. Late treatment retinas exhibited continued, albeit slowed, loss of sensitivity and signal fidelity among RGCs, 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退化疾病，始于视杆细胞丧失，随后是视锥细胞丧失，最终导致失明。基因疗法正在研发中，但视网膜功能如何依赖于干预时间尚不清楚。为了揭示这种依赖性，我们利用了一种能够进行人工基因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关键问题的能力变得复杂的变量，实现了最佳基因疗法的基准。在视杆细胞丧失25%、50%和70%时（分别为早期、中期和晚期）进行了完全基因拯救。早期和中期治疗将视网膜功能恢复到接近野生型水平，特别是视网膜神经节细胞（RGCs）的敏感性和信号保真度，视网膜神经节细胞是视网膜的“输出”神经元。然而，一些解剖学缺陷仍然存在。晚期治疗的视网膜中，RGCs的敏感性和信号保真度持续丧失，尽管速度减慢，同时还存在持续的胶质增生。我们得出结论，在视杆细胞丧失50%后进行的基因替代疗法不太可能将视觉功能恢复到正常水平。这对于实施基因疗法来挽救视力是至关重要的信息。
