Murphy Daniel P, Kolesnikov Alexander V, Montana Cynthia L, Khaja Zaid M, Liu Yu, Kefalov Vladimir J, Corbo Joseph C
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, CA 92617.
Proc Natl Acad Sci U S A. 2025 May 27;122(21):e2500446122. doi: 10.1073/pnas.2500446122. Epub 2025 May 21.
Acute knockout of the rod photoreceptor transcription factor delays retinal degeneration in multiple mouse models of blindness, but the downstream transcriptomic changes that mediate these therapeutic effects are unknown. Here, we show that acute knockout causes upregulation of a subset of cone genes in rods as well as downregulation of rod genes, including the rod-specific transcriptional repressor . We hypothesized that downregulation might mediate some of the therapeutic effects of knockout. Indeed, acute knockout of prevents photoreceptor degeneration and preserves visual function in mice with mutations in the catalytic subunit of the rod-specific phosphodiesterase (). Upregulation of , the cone-specific paralog of , in -knockout rods is required to prevent degeneration in mice, suggesting that this therapeutic effect is mediated, at least in part, by a gene-replacement mechanism. In contrast, acute knockout fails to prevent degeneration caused by loss- or gain-of-function mutations in Rhodopsin ( and ), whereas acute knockout delays degeneration in both models. Surprisingly, the therapeutic effect of acute knockout in mice does not depend on upregulation. These results suggest that acute knockout may exert its therapeutic effects via a mechanism independent of downregulation, perhaps by downregulating other rod genes. We conclude that acute knockout may be a promising gene-independent strategy for preventing photoreceptor degeneration in human patients.
杆状光感受器转录因子的急性敲除可延缓多种失明小鼠模型中的视网膜退化，但介导这些治疗效果的下游转录组变化尚不清楚。在这里，我们表明急性敲除会导致杆状细胞中一部分视锥细胞基因上调以及杆状细胞基因下调，包括杆状细胞特异性转录抑制因子。我们假设下调可能介导了敲除的一些治疗效果。确实，在杆状细胞特异性磷酸二酯酶催化亚基发生突变的小鼠中，急性敲除可防止光感受器退化并保留视觉功能。在敲除的杆状细胞中，视锥细胞特异性同源物的上调是防止小鼠退化所必需的，这表明这种治疗效果至少部分是由基因替代机制介导的。相比之下，急性敲除无法防止由视紫红质功能丧失或功能获得突变（和）引起的退化，而急性敲除在两种模型中均可延缓退化。令人惊讶的是，急性敲除在小鼠中的治疗效果并不依赖于的上调。这些结果表明，急性敲除可能通过一种独立于下调的机制发挥其治疗作用，也许是通过下调其他杆状细胞基因。我们得出结论，急性敲除可能是一种有前途的、不依赖基因的策略，用于预防人类患者的光感受器退化。
