Abstract
Purpose :
Inherited retinal degenerations (IRDs) represent a diverse group of disorders caused by mutations in over 200 genes that primarily affect the function of photoreceptor cells. Given that rod photoreceptor cell death is a common early feature in most IRDs, we previously performed an unbiased large-scale screening of rod survival using retinal organoids differentiated from induced pluripotent stem cell of rd16 mice that phenocopies Leber congenital amaurosis caused by CEP290 mutations and identified reserpine as a lead molecule (https://www.medrxiv.org/content/10.1101/2022.09.14.22279917v1). Reserpine could attenuate photoreceptor cell death in human organoids and rd16 mice. Here, we evaluated the effect of reserpine in P23H rhodopsin transgenic rats, a well-studied autosomal dominant model of retinal degeneration.
Methods :
P23H rhodopsin transgenic rats were intravitreally injected with reserpine or vehicle at postnatal day(P) 30 and 44. Retinal function was evaluated by optokinetic tracking (OKT), contrast threshold (CT) measurement and ERG, and structure was evaluated by OCT imaging. Eyes were enucleated for histological analysis.
Results :
Scotopic b-wave at P68 revealed higher amplitude in rats treated with reserpine compared to controls, even though scotopic a-wave, photopic b-wave, OKT and CT did not show a significant difference. Subgroup analysis on female rats revealed higher response in scotopic a- and b-wave, photopic b-wave at P68 and better CT at P53 and P67. OCT revealed enhanced retinal thickness in vertical and horizontal scan in female subgroup analysis. Larger number of rows were evident in the outer nuclear layer of rats treated with reserpine compared to control rats.
Conclusions :
Reserpine, a drug candidate for CEP290 retinal ciliopathy, was previously shown to act by modulating the balance between autophagy and ubiquitin-proteasome system. Our results indicate that reserpine could also attenuate photoreceptor degeneration in P23H rhodopsin transgenic rats, especially in females. Further studies are in progress; however, it appears that autophagy modulators may have broader impact on photoreceptor survival and suppress common cellular pathways leading to the photoreceptor cell death in different IRDs. Such drug candidates provide gene-agnostic therapeutic options for treatment of retinal diseases.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.