Assessing the effects of extracellular vesicles on a human in vitro dry AMD model

• Applicant: Professor Dr. Marius Ader
• Subject Area: Ophthalmology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493681544

Age related macular degeneration (AMD) is the leading cause for blindness in the elderly population and is classified into two forms of dry and wet AMD. Besides the loss of the light-sensing cone photoreceptors in the macula also the underlying retinal pigment epithelium (RPE) is severely affected in AMD pathology. While anti-VEGF therapies have been clinically established for wet AMD to inhibit detrimental vessel growth, no effective treatment is currently available for dry AMD. Though RPE replacement therapies are examined in clinical trials for late stage AMD, such approaches are characterized by challenges related to safety, transplant production, and costs. Thus, the development of alternative therapeutic approaches, particularly interfering at early disease stages, is of high clinical need. Extracellular vesicles (EVs) represent a cell free system that is currently investigated for the delivery of therapeutic molecules and prevention of pathological conditions in several diseases, thus representing a potential therapeutic treatment option also for AMD. EVs are involved in physiological and pathological cell-cell communication, their production and secretion is targeted, and they can activate or inhibit specific signalling pathways inside their target cells via different components including miRNAs, a class of complex gene regulatory RNA molecules. Indeed, EVs have been identified in the healthy and diseased retina, where they transferred biological signals between different cell types. In this study, we aim to assess the effects of human RPE-derived EVs on an in vitro model of RPE damage by (i) adapting our established oxidative stress model to human iPSC-derived RPE cells as a model of dry AMD, (ii) isolating and characterizing RPE-derived EVs, (iii) assessing the rescue potential of RPE-EVs on stressed human RPE cells, and (iv) identifying and evaluating potential therapeutic components within RPE-EVs using RNA profiling and bioinformatics analysis, and investigating the effects of identified miRNAs on stressed RPE cells. The results of this study will determine the therapeutic effect of EVs and miRNAs on damaged RPE cells as potential novel options for the treatment of dry AMD.

• DFG Programme: Research Grants