Abstract
Purpose :
The large genetic heterogeneity of inherited retinal degeneration (IRD) has limited the development of mutation-specific therapies, highlighting the need for therapeutic approaches targeting shared pathophysiologic pathways. We have previously demonstrated to importance of the Fas receptor as a major regulator of retinal cell death and inflammation in variety of ocular diseases. Fas mediated photoreceptor (PR) cell death is up-regulated in two different IRD mouse models, rd10 and P23H and is reduced by genetic inhibition of this pathway. Preliminary data from our laboratory suggested the protective effect of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204. The purpose of this study was to further define the protective effect of ONL1204 on PR degeneration in the rd10 and P23H mouse models of IRD.
Methods :
A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle alone. Fas activation was assessed by caspase 8 activity. Photoreceptor cell death was examined by TUNEL cell counts. Retinal structure and function were analyzed by immunohistochemistry (IHC), optical coherence tomography (OCT) and electroretinography (ERG) analysis. The activation of immune cells in the retina was evaluated by Iba1 staining on retinal sections and whole mount.
Results :
In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) photoreceptors, decreased caspase 8 activity, enhance photoreceptor cell counts, and improved visual function compared with vehicle treated fellow eyes. ONL1204 treatment also reduced immune cell activation in the retinas of both rd10 and P23H mice.
Conclusions :
Protective effect of pharmacologic Fas inhibition by ONL1204 in two distinct mouse models of retinal degeneration suggests that targeting this common pathophysiologic mechanism of cell death and inflammation represents a potential mutation-independent therapeutic approach to preserve the retina in patients with IRD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.