Development of advanced glycation end product (AGE)-breaking enzymes as a novel therapy for the treatment of diabetic retinopathy

PROJECT SUMMARY Diabetic retinopathy (DR) is a major complication associated with Type 1 and Type 2 diabetes. Approximately 20% of patients with diabetes develop DR. DR is the leading cause of blindness in the working age population (20-74 years old) and affects more than 6.6 million adults in the U.S. alone. Existing therapies primarily target vascular hyperpermeability, which is responsible for intraocular pressure increase and visual disturbances. While antibodies against VEGF (ranibizumab, aflibercept), have shown clinical benefit and are now widely used for DR treatment, only 50% of patients with diabetic macular edema receiving anti-VEGF treatment have appreciable clinical benefit. This underscores the need for better treatments that address the upstream pathology and can provide treatment for both forms of DR including those refractory to anti-VEGF therapy. Current FDA-approved treatments do not address pathogenic mechanisms driving the disease. The pathophysiology of DR is related to prolonged exposure to high blood sugar, leading to non-specific glycation of proteins and subsequent formation of toxic advanced glycation end-products (AGEs). Evidence suggests that accumulation of AGEs play a role in the vascular and inflammatory complications associated with diabetes, including DR. Revel Pharmaceuticals has developed a novel class of therapeutics designed to cleave one of the most significant AGEs present in the eye, carboxymethyl-lysine (CML), thus removing a significant driver of DR. Our goal in this Phase I grant is to optimize lead drug candidates and demonstrate enzyme activity on physiologically relevant DR substrates. Our specific aims are to (1) engineer CML oxidase to efficiently cleave CML modifications from physiological substrates (2) characterize CML oxidase activity on human retinal tissue. Successful completion of this Phase I SBIR project will yield the first therapeutic enzyme designed to remove and repair AGE damage in vivo. In Phase II, we will carry out in vivo efficacy and IND-enabling studies with our collaborators at Vanderbilt Ophthalmic Contract Research Organization (VO-CRO) to support an IND submission.