Investigating CFH Y402H phenotype in Retinal Pigment Epithelium (RPE) cells and retina in a novel co-culture model of Age-related macular degeneration (AMD)

01/01/2024 to 31/12/2026

To date, there is no adequate treatment for Age-related macular degeneration (AMD). The overall goal of our work is to understand in detail how one of the highest genetic risks, the Y402H polymorphism of complement factor H (CFH), contributes to AMD pathology. To this end, we have developed a new coculture model and have previously used it to demonstrate that retinal pigment epithelium (RPE) cells metabolically damaged by CFH loss (Armento et al. 2020) cause retinal degeneration in cocultured retinal explants (Armento, Murali et al. 2021). The coculture combines RPE cells with porcine retinal explants that closely resemble the human macula. In a next step, we are now using iPSC-derived RPE cells with 402Y / 402H-CFH variant in the coculture model to study the cellular processes in both RPE cells and the adjacent retina. Here, we aim to further elucidate CFH 402H-mediated changes in RPE cells, as well as retinal pathological changes induced by coculture with CFH-402H-iPSC-RPE cells. Via a multi-omic approach and functional validation in iPSC-RPE cells derived from AMD and age-matched donors, we aim in correlating signaling pathways with specific pathological changes. Moreover, using single-cell RNA sequencing in retinal explants, we will detect specific changes in gene expression in different retinal cell types. Important key factors will then be validated in coculture crosssections, as well as in human retinal tissue from genotyped AMD patients in the HEETR biobank (with Prof. Clark, Tübingen, Germany). The understanding of CFH Y402H driven AMD pathomechanisms is an important prerequisite for personalized therapeutic approaches.