LDL Modification and Diabetic Renal Dysfunction

DESCRIPTION (provided by applicant): The objective of this Phase I SBIR is to determine whether preventing LDL modification, in combination with an angiotensin converting enzyme (ACE) inhibitor, is of added benefit in arresting the development and/or slowing the progression of diabetic nephropathy in a mouse model of type 2 diabetes. The rationale for this application derives from evidence linking modified LDL to diabetic glomerulosclerosis; the imperfect protection provided by inhibitors of the renin-angiotensin system (RAS), particularly in type 2 diabetes and in later stage disease; and our recent work demonstrating that a small molecule that prevents LDL modification is reno-protective in db/db mice. Notably, this compound (designated GLY-022) lessens urinary excretion of albumin and of collagen IV, a marker of renal extracellular matrix accumulation, protects against reduction in filtration function, prevents renal overproduction of TGF-beta1 protein, and restores glomerular nephrin in db/db mice. These findings suggest that GLY-022 may have a therapeutic role in the treatment of renal disease in human diabetes. Since RAS inhibitors are widely used in diabetic patients with increased albumin excretion and/or decreased glomerular filtration function, it is important to document that any proposed novel intervention strategy for diabetic renal disease confers added benefit on a background of treatment with an RAS inhibitor before lengthy and expensive clinical development of new therapies is undertaken. The specific aims of this Phase I project are to: a) Evaluate and compare the effect of lisinopril and of GLY-022, alone and in combination, on the development and progression of diabetic nephropathy in db/db mice; b) Perform dose response efficacy studies and determine optimum dosing range for meaningful effect of GLY-022, when added to chronic lisinopril therapy, on renal structure and function in diabetic rodents; and c) Assess the ability of GLY-022 added early versus later in the course of diabetes to prevent or ameliorate the structure/function changes of overt nephropathy in diabetic rodents treated with lisinopril. Positive results in this feasibility project will provide strong impetus to pursue a Phase II project and clinical development of this compound.