REDUCING RENAL TGF-B IN DIABETIC GLOMERULOSCLEROSIS

DESCRIPTION (provided by applicant): The objective of this project is to develop for clinical use a novel pharmacologic agent for the prevention/treatment of diabetic glomerulosclerosis. The rationale for this application derives from our work encompassing in vitro and in vivo studies that have elucidated the important role of nonenzymatically glycated albumin in the pathogenesis of diabetic nephropathy, delineated molecular messengers responsible for glycated albumin-induced stimulation of glomerular extracellular matrix production, and demonstrated that reducing the burden of glycated albumin with the small molecule designated 22CPPA attenuates all of the structural and functional changes of diabetic kidney disease in the db/db mouse. 22CPPA inhibits the condensation of glucose with reactive amino groups in albumin and significantly lowers serum concentrations of glycated albumin in hyperglycemic, diabetic animals, resulting in a reduction of the glomerular over-expression of TGF-Beta1 and prevention of glomerulosclerosis and renal insufficiency even when hyperglycemia prevails. Based on these findings, we propose that targeting the over-expression of glomerular TGF-Beta1 through inhibiting the excess nonenzymatic glycation of album in diabetes is a viable therapeutic strategy for preventing the progression of diabetic nephropathy and that 22CPPA is a novel clinical candidate for treatment of this morbid complication of diabetes. The Phase I goals of this project are to delineate the dose-response profile of 22CPPA on the therapeutic targets, and to examine its acute lethality/toxicity. During Phase I we will work with a contract manufacturer for manufacture of GMP grade 22CPPA, which will be used for the formal animal toxicology and pharmacokinetics that will be performed in Phase II to support initial exposure of humans to the compound in clinical Phase I (safety) and Phase II (early efficacy) trials that also will be undertaken in the Phase II project. Animal toxicology will be conducted with the same lot of GMP grade 22CPPA that is used in clinical trials arid will be commensurate in duration and dosage with the clinical testing to be performed. The specific Aims of time Phase I project, which will constitute Milestones, are to: 1) Perform dose-response efficacy studies amid determine optimum dosing range for meaningful reduction of glomerular TGF B1 and plasma glycated albumin in diabetic rodents; 2) Conduct in vivo studies of acute toxicity/lethality of 22CPPA; and 3) Begin process development with a contract manufacturer for clinical grade (GMP manufactured) 22CPPA that meets requirements with respect to best yield/minimal side products, and concurrently plan for relevant analytical development amid testing, validation, purity, and stability so as to obtain drug substance that is suitable for formal animal toxicology to support use in human subjects, and for conduct of Phase I arid II clinical trials during the Phase II project. PROPOSED COMMERCIAL APPLICATIONS: This project seeks to develop for clinical use a novel pharmacologic agent for the prevention/treatment of diabetic glomerulosclerosis, and is expected to result in commercialization partnering.