Mechanisms of photoreceptor protection upon targeting the pathway.

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.