Blindness caused by degeneration of the retinal pigment epithelium (RPE) represents one of the most pressing unmet needs in medicine. The RPE is a metabolically specialized monolayer essential for photoreceptor survival, and its dysfunction leads to ‘RPE diseases’, such as rare inherited retinal diseases (IRD) and common age-related macular degeneration (AMD). A striking but unresolved observation is that some RPE regions, especially the macula, are highly vulnerable to degeneration, while others remain preserved for decades. The molecular and metabolic basis of this selective degeneration is unknown, yet understanding it is key to precision medicine in RPE diseases.

The main goal of RPE-GUIDE is to decipher why specific regions of the human RPE are selectively vulnerable to disease. Specifically, we will (1) define regional subpopulations of healthy human RPE by integrating molecular-metabolic maps; (2) uncover actionable disease pathways in IRD using RPE “cell villages”, a transformative stem cell approach for disease modelling; and (3) identify bioliquid biomarkers for IRD. By bridging maps, models, and mechanisms, RPE-GUIDE will establish a new foundation for improved genetic diagnostics, gene-agnostic therapies - relevant for many patients - and innovative biomarkers for patient stratification and monitoring.

Given the pivotal role of the RPE in vision, the long-term goal is to guide precision medicine for blindness.