PARP inhibitor therapy for acute myocardial infarction

描述(申请人提供)：尽管ST段抬高心肌梗死(STEMI)患者接受再灌注治疗已有明确的益处，但恢复受损心肌的血流似乎与许多有害影响有关，包括微血管损伤、心律失常和心肌细胞坏死的扩大。由氧化剂分子的快速生成引发的细胞内能量和炎症过程的破坏似乎在随后的心肌细胞损伤中发挥了核心作用。 氧化剂诱导的DNA单链断裂激活核酶多聚(ADP-核糖)聚合酶(PARP)，启动耗能、低效的细胞代谢循环。由此导致的二核苷酸池的枯竭减缓了糖酵解和线粒体呼吸的速度，减少了ATP的合成，并导致细胞功能障碍和坏死。利用我们专有的PARP抑制剂INO-1001(Ki=15纳摩尔)，我们已经证明，在左冠状动脉结扎导致的急性STEMI猪中，PARP抑制减少了65%的心肌梗死。拟议中的Fast Track应用的中心目标是确定INO-1001作为STEMI在初次经皮冠状动脉介入治疗(血管成形术或支架)中的潜在辅助治疗的临床疗效。在第一阶段SBIR中，我们将确定PARP在STEMI患者接受直接经皮冠状动脉介入治疗(PCI)时细胞功能障碍和炎症反应的调节作用。在一项前瞻性、多中心、随机、开放标签、剂量范围的研究中，我们将研究45名接受直接经皮冠状动脉介入治疗的急性前壁或下壁心肌梗死患者。这项试验将在10到15家美国医院进行，由TIMI研究小组主席尤金·布朗瓦尔德教授领导。INO-1001治疗将在开始再灌注治疗(主要是经皮冠状动脉介入治疗)之前，即在I/R损伤发生之前，给予两个剂量水平(或安慰剂)。我们期望这些研究证明：(A)INO-1001呈剂量依赖性地抑制STEMI患者细胞PARP活性，以及(B)STEMI患者INO-1001的药代动力学与健康志愿者相似。这些研究将为由SBIR资助的2期330名患者进行的多中心TIMI领导的研究提供科学基础，以确定INO-1001在缩小急性STEMI患者梗死范围方面的有效性。

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.