gms | German Medical Science

Age-related macular degeneration (AMD) is the most common blinding disease in the western world and is currently incurable. One of the main pathologic features of AMD is the retinal pigment epithelium (RPE) degeneration as well as the accumulation of autofluorescence (lipofuscin). We have developed a model system that recapitulates some AMD features in vitro where feeding human RPE monolayers in culture with porcine photoreceptor outer segments (POS) leads to accumulation of autofluorescent granules similar to lipofuscin in vivo, mimicking RPE cellular stress and disease. Interestingly, our preliminary results in RPE cells showed that overexpression of the transcriptional regulator NRF2, as well as treatment with dimethyl fumarate (DMF), a known NRF2 activator, can prevent the formation and/or resolve of POS-derived autofluorescent granules, suggesting that this pathway and the proteins it controls are important for autofluorescent granule formation. Thus, our hypothesis is that induction of an anti-oxidative stress response could represent a therapeutic strategy in early/intermediate AMD. Focusing on repurposing clinically approved drugs that are described to be pharmacological modulators of NRF2, such as Curcumin, Bardoxolone methyl and Sulforaphane, we tested these compounds in our in-vitro model, and evaluate their ability to decrease autofluorescent granules formation, as compared with DMF. Our first results point out Curcumin as an emerging pharmacological approach to decrease the accumulation of autofluorescence. Further studies will also include human phenolic metabolites library screening of NRF2 activators. We are also validating protocols for NRF2 activation in RPE cells by using western blot, immunofluorescence and gene expression assays. Overall, this project could represent a major step forward, not only for AMD treatment but also for other age-related diseases, and consequently, will contribute to a healthier ageing.

Funding: La Caixa Foundation (HR22-00569 NASCENT); Fundação para a Ciência e Tecnologia (Portugal) through the R&D unit iNOVA4Health (UIDB/04462/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020); COST Action BenBedPhar (CA20121).