PARP inhibitor therapy for acute myocardial infarction

DESCRIPTION (provided by applicant): Despite the established benefits of reperfusion therapy among patients presenting with ST elevation myocardial infarction (STEMI), restoration of flow to the injured myocardium appears to be associated with a number of deleterious effects, including microvascular injury, arrhythmias, and extension of myocyte necrosis. The disruption of intracellular energetics and inflammatory processes triggered by the rapid generation of oxidant molecules appear to play a central role in the consequent myocyte injury. Oxidant-induced DNA single strand-breakage activates the nuclear enzyme poly (ADP-ribose) polymerase (PARP) and initiates an energy consuming, inefficient cellular metabolic cycle. The resultant depletion of dinucleotide pools slows the rate of glycolysis and mitochondrial respiration, reducing ATP synthesis and leading to cellular dysfunction and necrosis. Utilizing our proprietary PARP inhibitor INO-1001 (Ki=15 nanomolar), we have demonstrated that PARP inhibition reduces myocardial infarction by 65 percent in pigs with acute STEMI induced by left coronary arterial ligation. The central objective of the proposed Fast Track application is to establish the clinical efficacy of INO-1001 as a potential adjunctive therapy for STEMI in the setting of primary percutaneous coronary intervention (angioplasty or stenting). In the PHASE 1 SBIR we will establish the role of PARP in the regulation of cellular dysfunction and inflammatory response in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). In a prospective, multi-center, randomized, open-label, dose-ranging investigation we will study 45 human volunteers with acute anterior or inferior MI undergoing primary PCI. The trial will be conducted in 10-15 American hospitals, led by the Chairman of the TIMI Study Group, Professor Eugene Braunwald. INO-1001 therapy at two dose levels (or placebo) will be administered before the initiation of reperfusion therapy (primary PCI), i.e., prior to the onset of I/R injury. We expect these studies to demonstrate (a) that INO-1001 dose-dependently inhibits cellular PARP activity in patients with STEMI, and (b) that the pharmacokinetics of INO-1001 in STEMI patients are comparable to those in healthy human volunteers. These studies will provide the scientific foundation for a PHASE 2 SBIR funded 330 patient, multicenter, TIMI-led investigation to establish the efficacy of INO-1001 in reducing infarct size in patients acutely presenting with STEMI.