PARP inhibition for thoraco-abdominal aneurysm surgery

描述（由申请人提供）： 缺血-再灌注（I/R）引起组织损伤和全身炎症反应综合征（SIRS）。氧化剂影响这些变化的机制最近被归因于它们对基因组完整性的影响。氧化剂快速诱导DNA单链断裂，其激活核酶聚（ADPribose）聚合酶（“PARP”）。PARP反过来催化ADP-核糖的能量消耗聚合，导致NAD消耗、ATP消耗、坏死和器官衰竭。PARP激活还强烈上调促炎细胞因子、趋化因子和内皮细胞粘附分子的表达。阻断PARP或其基因缺失在再灌注损伤和炎症的细胞和动物模型中具有深刻的保护作用，但没有关于PARP临床作用的数据。我们现在建议测试的假设，PARP抑制可以有利地影响I/R损伤和SIRS的结果在man. To解决这个假设，我们将利用一个独特的候选药物（一种新型的纳摩尔有效PARP抑制剂称为INO-1001）和高度控制的I/R期间提供的胸腹部动脉瘤（TAA）的择期修复。这种外科手术会产生严重的组织损伤，可能导致肾和肺功能不全、截瘫和死亡。在我们的FASTTRACK提案的当前I期组成部分中，我们将在接受TAAA修复的人群中确定INO-1001的安全性特征和药代动力学（PK）。我们将通过在n= 17例受试者中进行前瞻性、双盲、随机、单中心研究来实现这一目标。INO-1001的给药将在术前开始，即在器官损伤发生之前，并持续4天，再灌注和诱导全身炎症反应的关键期，以重复推注给药方案（100和400 mg INO-1001 q12 h）给药。主要临床终点为安全性和药代动力学。安全性研究将侧重于生化、血液学和心血管终点。药代动力学研究将确定INO-1001的半衰期和组织分布是否与健康人群中定义的参数不同。FDA已经批准了这项研究的快速IND批准。

DESCRIPTION (provided by applicant): Ischemia-reperfusion (I/R) produces tissue injury and systemic inflammatory response syndrome (SIRS). The mechanism by which oxidants effect these changes has recently been ascribed to their impact on genomic integrity. Oxidants rapidly induce DNA single strand breaks that activate the nuclear enzyme poly (ADPribose) polymerase ("PARP"). PARP in turn catalyses an energy-consuming polymerization of ADP-ribose, resulting in NAD consumption, ATP depletion, necrosis, and organ failure. PARP activation also strongly upregulates expression of pro-inflammatory cytokines, chemokines, and endothelial cell adhesion molecules. Blockade of PARP, or its genetic deletion, is profoundly protective in cell and animal models of reperfusion injury and inflammation, but there are no data on the clinical role of PARP. We now propose to test the hypothesis that PARP inhibition can beneficially influence the outcome of I/R injury and SIRS in man. To address this hypothesis, we will utilize a unique drug candidate (a novel nanomolar potent PARP inhibitor termed INO-1001) and a highly controlled period of I/R afforded by elective repair of thoracoabdominal aneurysm (TAA). This surgical procedure produces profound tissue injury that may result in renal and pulmonary insufficiency, paraplegia, and mortality. In the present PHASE I COMPONENT OF OUR FASTTRACK proposal, we will establish the safety profile and pharmacokinetics (PK) of INO-1001 in a population undergoing TAAA repair. We will address this objective by carrying out a prospective, double-blind, randomized, single-center investigation in n= 17 subjects. Administration of INO-1001 will be initiated preoperatively, i.e. prior to the onset of organ injury, and continued for 4 days, the critical period of reperfusion and induction of a systemic inflammatory response, administered in a repeated bolus dosing regimen (100 and 400 mg INO-1001 q12h). The primary clinical endpoints will be safety and pharmacokinetics. Safety studies will focus on biochemical, hematologic, and cardiovascular endpoints. Pharmacokinetic studies will establish whether the half-life and tissue distribution of INO-1001 differ from parameters defined in a healthy population. The FDA has granted Fast-Track IND approval to this investigation.