Poly(ADP-ribose) synthetase inhibition and diabetes

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DESCRIPTION (provided by applicant): The current application represents the Phase I component of a Fast-Track SBIR Grant by Inotek Corporation, proposing to establish a proof-of-concept of the involvement of poly (ADP-ribose) polymerase (PARP) activation in the pathogenesis of Type I diabetes mellitus and its complications, and to test the effect of pharmacological inhibition of PARP in murine models of diabetes and its complications. As preliminary data the investigators present evidence in cultured islet cells, showing that PARP activation plays a key role in the development of oxidant-mediated islet cell injury and in diabetic cardiovascular complications. The investigators now have synthesized a potent PARP inhibitor as a lead developmental candidate agent for the experimental therapy of beta cell destruction associated with autoimmune diabetes as well as its complications. The central aim of Phase I component is to perform proof-of-concept in vivo studies in diabetic rodents. If these studies confirm that Inotek's PARP inhibitor is remarkably effective in streptozotocin and NOD models of diabetes, and protects against diabetic complications, a Phase II component will be triggered, which will focus on formal pre-clinical safety testing. In the Phase II component of the current SBIR application, the investigators propose to perform pre-clinical safety studies with GLP quality material. A GMP quality synthesis of the compound will be developed and the compound formulated as an oral drug. In addition, the investigators propose formal safety studies and, for the second year of the project an accelerated carcinogenicity trial in the P53 mice. These latter studies are essential for the future introduction of a potent PARP inhibitor into the clinical management of diabetes mellitus. Taken together, the investigators request funds from the NIH to develop a potent, orally bioavailable PARS inhibitor, which is expected to be effective in reducing the incidence of type I diabetes, and in attenuating hyperglycemia-induced vascular complications (in established Type I and Type II diabetes).