Abstract
Purpose :
Approximately 18 million Americans aged 40 and older are diagnosed with early-stage age-related macular degeneration (AMD), with no available treatment to prevent disease progression to the late stages of AMD that cause irreversible vision loss. Recent studies showed that metabolic alternations in photoreceptors cause AMD-like pathologies in mice. Elucidating pivotal metabolic regulators in photoreceptors that contribute to AMD holds promise for the identification of novel therapeutic targets to prevent disease progression. In this study, S6 kinase 1 (S6K1) is identified as one such regulator with a promising treatment efficacy.
Methods :
We employed both genetic and pharmacological approaches to reduce the levels of S6K1 in murine retinas to assess if AMD-like pathologies are alleviated. Fundus imaging, histological analyses, lipid profiling and RPE phagocytosis assay were performed to determine the progression of AMD-like pathologies. Furthermore, the pharmacological application has been examined for its duration in S6K1 gene silencing and its safety in two large animal models including non-human primates (NHPs).
Results :
Fundus analysis of 12-month-old mice revealed that 20% (n=16 mice) of our AMD mice developed geographic atrophy (GA) and 5% developed neovascular (NV) pathologies. In contrast, genetic removal of S6K1 in our AMD model did not lead either to GA or NV pathologies (n=25). Immunohistochemistry showed that Apolipoprotein E, one of the major components of drusen in AMD patients, was greatly reduced in the Bruch’s membrane of mice with genetic deletion of S6K1. Similar results were seen with pharmacological reduction of S6K1 in the AMD mouse model. Furthermore, both approaches to reduce S6K1 levels in mouse retinas also alleviated RPE phagocytic problems. The pharmacological approach to reduce S6K1 level showed a prolonged (up to 3 months) and stable gene silencing efficiency in NHPs and pigs and neither microglia activation nor gliosis was observed in treated eyes.
Conclusions :
Currently, there is no treatment that prevents disease progression in early-stage AMD patients. Our data indicates that reducing S6K1 in the retina prevents AMD-like progressions and alleviates pathologies in an AMD mouse model. Reduction of S6K1 levels may be a viable new therapy for the prevention and treatment of AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.