Abstract
Purpose :
Inherited retinal degeneration (IRD), a common cause of blinding disease in the United States, is a class of retinal diseases resulted from mutations in nearly 300 different genes. This extreme genetic heterogeneity has limited the development of mutation-specific therapies, and there is an urgent need for approaches targeting broadly shared pathophysiologic pathways in IRD patients. The CD95 death receptor, also known as Fas, has been reported as a contributor to retinal cell death and inflammation in a wide variety of ocular diseases. The purpose of the study is to examine the effects of genetic inhibition of Fas on retinal degeneration in 2 distinct IRD mouse models, P23H and rd10, as a proof-of-concept study of targeting Fas pathway as a novel mutation-independent approach to IRD.
Methods :
The basal levels of Fas activation and inflammation in the P23H, rd10 and C57 (wild-type) controls were evaluated by TUNEL cell counts, caspase 8 activity assay, rt-PCR, and IHC. Genetic inhibition of Fas was achieved by crossing Fas-lpr, a functionally Fas-deficient mouse line, with P23H or rd10 to generate P23H/Fas-lpr and rd10/Fas-lpr mice. Retinal structure and function were evaluated by IHC, OCT and ERG analysis. The activation of microglia and the production of inflammatory cytokines were also assessed.
Results :
Retinas from both P23H and rd10 mice showed elevated transcript and protein levels of Fas receptor, increased caspase 8 activity and TUNEL (+) photoreceptor cells as compared to wild-type C57 mice. Microglial activation and migration to photoreceptor layer was detected in the retinas of both P23H and rd10 mice, consistent with increased levels of inflammatory cytokines in these two models. Genetic Fas deficiency resulted in preservation of photoreceptor viability and retinal functions in both P23H and rd10 mice. Microglial activation and cytokine production was also reduced in both P23H/Fas-lpr and rd10/Fas-lpr mice compared with age-matched controls.
Conclusions :
Our observation of protective effect of genetic Fas inhibition in two different mouse models of retinal degeneration suggests that while the individual IRD mutation may be specific, the retina’s response to the different stress appears to be shared and driven by cell death-inducing receptor Fas. Deletion of Fas might represent a potential mutation-independent therapeutic approach to preserve retinal structure and function in patients with IRD.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.