Novel Therapeutic for Preventing Fuchs Endothelial Corneal Dystrophy

About This Grant

PROJECT SUMMARY/ABSTRACT Fuchs endothelial corneal dystrophy (FECD) is a polygenic disease that affects 6.1 million Americans over 40 years of age. FECD is the leading indication for corneal transplant surgery in the U.S. Although the condition can be diagnosed early, it requires corneal surgery because no available therapy prevents disease progression. Unfortunately, the availability of donor corneal tissue is extremely limited (only 1 cornea is available for every 70 needed worldwide), and the risks of donor tissue failure (immediate risk) and graft rejection and failure (lifetime risks) are significant. In addition to preserving sight and circumventing the need for surgical intervention, medical therapy (e.g., eye drops) would avoid the following key issues: 1) high medical costs, 2) lack of available corneas, 3) lost productivity costs, and 4) long-term care costs associated with corneal transplantation. The need to develop an effective nonsurgical intervention is therefore urgent. In exciting preliminary studies, the S5G Therapeutics, Inc. research team—in tandem with experts at the University of Iowa—recently demonstrated that a cell surface iron (Fe) influx protein, transferrin receptor 1 (TFR1), is overexpressed in the corneal endothelial cells (CECs) of FECD patients. TFR1 overexpression in FECD is linked specifically to ferroptosis—a pathogenic mechanism of cell death characterized by lipid peroxidation and intracellular Fe accumulation. The overall goal of this SBIR Phase I project is therefore to develop, validate, and determine the feasibility of a targeted pharmacotherapeutic that is independent of specific gene mutations causing disease and that prevents the progression of clinical disease and need for surgery in FECD patients. Our screen of hundreds of anti-ferroptosis antioxidants indicated that the top performer was ubiquinol (the active and reduced form of coenzyme Q10). Our published data indicate strongly that ubiquinol prevents ferroptosis in FECD models. Thus, our central hypothesis is that therapies containing ubiquinol to target lipid peroxidation will greatly reduce cell death across a spectrum of FECD mutations and will prevent disease progression and the need for surgery. Ubiquinol is sensitive to heat and light with a very short half-life, and we have achieved a nanoparticle (NP)-based pharmacoengineering solution to render it practically useful. We intend to prove the feasibility of this novel approach via two Specific Aims: 1) Optimize the dosing of ubiquinol-loaded TFR1-targeted NPs versus controls, and 2) Determine the optimum time to initiate treatment with ubiquinol TFR1-targeted NPs versus controls. The approach is innovative, in that we will use a novel disease-dependent targeting strategy to develop mechanism-specific, first-in-class anti-ferroptosis antioxidant NPs to prevent FECD progression without surgery. The expected Phase I outcome is advancement of a novel eye drop to slow FECD progression and reduce the need for corneal transplant surgery, and will yield the best dosing frequency and initiation point for a Phase II validation/demonstration of topical use in a preclinical small-animal trial. Phase II success will be the basis for Phase IIB/Phase III studies focused on testing this treatment in human clinical trials and attaining ultimate commercial deployment.