Downregulation of Transducin Delays Photoreceptor Degeneration in P23H Rhodopsin Retinitis Pigmentosa

Abstract

In inherited blinding diseases, such as Retinitis Pigmentosa (RP), photoreceptors progressively degenerate, eventually leading to blindness. Unfortunately, effective treatments to prevent or delay vision loss do not exist for most RPs. Dark rearing is known to delay retinal degeneration in preclinical models of RP. Therefore, in this study we evaluated the impact of reducing photoreceptor light signaling on RP progression. This was done by genetically ablating or downregulating transducin in rods or cones in a preclinical RP model carrying a single P23H mutant rhodopsin allele (P23H mice). Ablating rod transducin significantly improved photoreceptor survival in the P23H retina. Additionally, downregulating rod transducin promoted photoreceptor survival and improved rod light response in P23H mice. Remarkably, male P23H mice retained robust cone function until old age in the absence of rod transducin whereas female P23H carriers experienced significantly faster loss of cone function. In these females, reducing cone transducin improved cone function whereas the same treatment was not effective in male P23H carriers. Our data demonstrate that reducing rod or cone transducin expression in P23H mice improves the survival and function of rods and cones, and suggest transducin downregulation as an effective therapeutic strategy to delay photoreceptor degeneration in RP.