PARP Inhibitors for Acute Renal Failure

DESCRIPTION (provided by applicant): The objective for the proposed study is to determine the feasibility of using novel small molecule poly(ADP-ribose) polymerase (PARP) inhibitors for treating acute renal failure (ARF), the most costly kidney disease in hospitalized patients with no drug currently approved for the indication. We believe PARP inhibition may offer a novel approach to treat kidney ischemia, based on our research that demonstrates the efficacy of PARP inhibitors on reducing various ischemia-reperfusion injuries in animal models, including cerebral ischemia, myocardial infarction, and cardiac arrest. Guilford Pharmaceuticals Inc. has identified a series of water-soluble PARP inhibitors that 1) achieved high level accumulation in plasma, heart and brain after intravenous or oral dosing and 2) provided neuroprotection in a rat model of stroke, provided cardioprotection in a rat model of heart ischemia and increased survival in a rat model of cardiac arrest. We intend to test our proprietary PARP inhibitors in a rat model of kidney ischemia. In collaboration with Dr. Babu Padanilam (University of Nebraska), we demonstrated that intravenous treatment with our leading PARP inhibitor, GPI 15427, ameliorates the course of ischemic renal injury by reducing serum creatinine and blood urea nitrogen levels. Dr. Padanilam's lab also found that mice with a PARP-1 gene deletion are resistant to renal ischemia injury, further validating the drug target. To achieve the objective of the current study, we have designed a series of experiments that are aimed at 1) optimizing the pharmaceutical properties of GPI 15427 for renal use; 2) profiling the pharmacokinetic and toxicological effect of the GPI 15427 on kidney metabolism; and 3) determining the optimal dose-effect relationship of GPI 15427 in the rat model of kidney ischemia by both intravenous and oral administration. We expect results from this phase I study will yield information for assessing the prospect of phase II preclinical development towards clinical trials and commercialization of PARP inhibitors for treating ARF.