Modulating Ferroptosis in Fuchs Endothelial Corneal Dystrophy

PROJECT SUMMARY/ABSTRACT Fuchs endothelial corneal dystrophy (FECD) affects 6.1 million Americans over 40 years of age, is the leading indication for corneal transplant surgery, and although it can be diagnosed early it requires corneal transplantation because no medical therapy can prevent its progression. Genetic factors, abnormal cell-matrix interactions, and oxidative stress induced by ultraviolet light-A (UVA) all contribute to FECD, but the precise mechanisms inciting cell death remain poorly understood. We present novel and compelling evidence that ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, is a key driver of corneal endothelial cell (CEC) death in FECD. Specifically, increased reactive iron (Fe2+) concentrations, lipid peroxidation, and expression of transferrin receptor (TFR1, a ferroptosis-specific marker) occur in corneal endothelial tissue from FECD patients. These data are foundational and guide us to further investigate drivers of ferroptosis in FECD. Pathological extracellular matrix features in FECD (e.g., guttae) are recognized risk factors associated with premature CEC death in FECD. Exciting preliminary data indicate that FECD patients have increased TFR1 expression surrounding guttae compared with adjacent cells, which compels us to study the role of guttae in driving ferroptosis. Additionally, UVA exposure is a risk factor that drives FECD progression and triggers ferroptosis in other exposed tissues (e.g., skin). Exciting preliminary data demonstrate that UVA increases Fe2+ concentrations, which leads directly to Fenton reactions and oxidative damage in lipid membranes with subsequent ferroptosis-induced cell death in FECD. Our overall goal is to develop a preventive medical therapy (e.g., eye drops) that preserves corneal function, protects against vision loss, and increases quality of life without surgery for FECD patients. To achieve this, we will target iron-mediated lipid peroxidation that is involved in FECD progression. Our team is well positioned to conduct this research due to our expertise in ferroptosis and animal models of FECD and phamacoengineering. The overall objectives of the proposed research are to investigate how guttae and UVA drive ferroptosis in FECD and develop anti-ferroptosis drug therapy using in vitro and in vivo FECD models. Our central hypothesis is that FECD genetics predispose CECs to ferroptosis, and that guttae eruption through the CEC monolayer and UVA exposure both drive aberrant reactive iron to accumulate in cells and cause ferroptosis. Guided by strong preliminary data, the hypothesis will be tested through the following specific aims: 1) Define the interplay between guttae and ferroptosis in FECD; 2) Determine how UVA mediates ferroptosis in FECD; and 3) Modulate ferroptosis to mitigate cell loss in FECD. The approach is innovative in that we will utilize well-characterized human tissues and primary cells from FECD patients, multiple animal models of FECD, and state-of-the-art technical assays. The proposed research is significant because it will clarify the mechanism of how genetic and environmental risks lead to premature cell death through ferroptosis in FECD, and advance targeted drug therapy to prevent or delay its progression.