AMD_Prog · Lysophagy as a new strategy for neuroprotection in dry AMD

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly, a disease mainly driven by dysfunction of highly specific retinal pigment epithelial (RPE) cells. A key hallmark of ageing, dysregulated autophagy and impaired lysosomal clearance, is strongly implicated in AMD pathology, leading to cellular waste accumulation and damage. A certified treatment for dry AMD remains unavailable, highlighting an urgent need for novel therapeutic strategies. The central hypothesis of my project is that targeting lysophagy (selective degradation of damaged lysosomes) presents a substantial therapeutic prospect for AMD. To test this, I will utilise a cutting-edge human induced pluripotent stem cell (iPSC) derived RPE system. These cells offer a superior, physiologically relevant model that precisely recapitulates key AMD features, providing a powerful platform for disease research and drug discovery that is unmatched by conventional models. I will first delineate the role of lysophagy in AMD pathophysiology using established chemical models of degeneration, with Sodium Iodate and Hydroquinone. Building upon this, a key objective is to establish a more robust, precise model using N-retinylidene-N-retinylethanolamine (A2E), the key component of lipofuscin that accumulates in RPE cells during AMD, and a custom blue light illuminator to induce acute photo-oxidative damage. I will use these stress models to test whether RPE cells differentiated from a patient carrying risk alleles for AMD are more sensitive to the in vitro AMD models. Next, I will perform a screen for potential lysophagy-inducing compounds. The ultimate goal is to identify novel, stable, and affordable neuroprotective compounds that alleviate retinal degeneration in iPSC-derived RPE cells. This project will elucidate lysophagy mechanisms in a human-relevant system, advancing AMD research, aiding novel therapeutic interventions against age-related neurodegenerative diseases.