LDL Modification in Diabetic Complications

DESCRIPTION (provided by applicant): This Phase II project will advance to the clinical stage the novel pharmacologic agent GLY-022 for microvascular complications of diabetes by expanding in vivo studies on nephropathy to the streptozotocin diabetic rat and on retinopathy in the STZ-diabetic rat and in the db/db mouse, by assessing bioavailability, pharmacokinetics, and acute lethality, and by completing the milestones requisite for submission of an IND (Investigational New Drug) application, which include preparation of a GMP (Good Manufacturing Practice) lot of drug substance and formal toxicity, toxicology, toxicokinetic and safety studies with GMP-manufactured material. The rationale for this project derives from our work demonstrating that inhibiting LDL modification with GLY-022 is reno-protective in db/db mice and from results of the Phase I SBIR feasibility studies to evaluate if GLY-022 confers added protection on a background of chronic treatment with a inhibitor of the RAS (renin angiotensin system). These data support the hypothesis that GLY-022 is a viable clinical candidate for further protection against decline in renal filtration function in patients with diabetes being treated with RAS inhibitors. Additionally, and not anticipated as part of the Phase I studies, we obtained preliminary data suggesting that GLY-022 may be of benefit in diabetic retinopathy. The Phase I goals of this project were to examine effects of GLY-022 and an ACEI (angiotensin converting enzyme inhibitor), alone and in combination, on designated therapeutic targets and renal structure/function parameters, with the anticipation that positive results from these feasibility studies would provide strong impetus to pursue a Phase II project and clinical development of this compound. Based on achievement of the Phase I project milestones, we propose proceeding to the Phase II project which encompasses further studies for nephropathy and retinopathy indications, bioavailability, pharmacokinetic and lethality studies, and formal animal toxicology, safety and genotoxicity studies conducted with a fully validated GMP-lot of GLY-022. Complications affecting the kidneys and eyes are common and serious problems in patients with diabetes, and require innovative strategies for prevention and treatment. This Phase II SBIR project will advance to the clinical stage a novel compound that prevents modifications of lipoproteins that occur in diabetes and that contribute to the development of these complications.