Soluble Epoxide Hydrolase Inhibitor GSK2256294 for Acute Ischemic Stroke

项目摘要 拟议的翻译研究将确定GSK2256294的保护效果，一种FDA- 批准的可溶性环氧化物水解酶(SEH)抑制剂。抑制sEH可增加其内源性水平 底物二十碳三烯酸酯(EETs)，是一种具有多种机制的内源性脑组织脂质介质 对中风有益的作用，包括血管扩张、细胞保护、抗炎和抑制 对血小板聚集的影响。来自我们小组和其他人的大量证据表明，sEH抑制和基因 基因缺失减少实验性脑缺血再灌注损伤后脑梗塞面积和改善功能预后 大脑。在实验性缺血性卒中中，sEH失活的好处已经在年轻和 老年糖尿病和高血压雄性和雌性小鼠。重要的是，sEH中功能突变的获得 一种名为EPHX2的基因与人类缺血性中风风险增加和预后恶化有关， 然而，功能丧失突变的携带者降低了中风的风险，改善了预后。我们有 最近完成了使用GSK2256294治疗蛛网膜下腔动脉瘤患者的Ib期临床试验 出血(SAH)。试验证明，口服GSK2256294 10天是安全有效的 SAH危重患者可耐受。尽管没有疗效方面的动力，这项试验也显示了 相关功能结果的改善。拟议的研究将测试GSK2256294在 NINDS卒中前临床评估网络(SPAN)使用暂时性大脑中动脉闭塞(TMCAO)模型 幼年成年和老年2型糖尿病小鼠。PI将参加SPAN指导委员会，出席所有 Span会议并与所有获奖地点、协调中心(CC)和NINDS协作 计划工作人员实现SPAN计划的目标。GSK2256294将由一种高度 有经验的合同研究机构(中银科学)，并将提供足够的金额 通过整个SPAN网络进行并行测试。PI将与CC一起验证活动、集中度和 GSK2256294的溶解度，并以随机和盲法测试其在tMCAO模型中的疗效。这个 长期目标是支持在急性缺血性中风(AIS)的临床试验中使用GSK2256294和Advantage 它在AIS患者中的应用。因为GSK2256294已经获得了FDA的批准，并具有既定的安全性 在人类中的记录，包括出血性中风患者，它可以迅速推进到临床试验中进行测试 如果通过SPAN网络的严格测试确认了AIS的有效性。

Project Summary The proposed translational studies will determine the cereroprotective efficacy of GSK2256294, an FDA- approved soluble epoxide hydrolase (sEH) inhibitor. Inhibition of sEH increases the endogenous levels of its substrate epoxyeicosatrienoates (EETs), which are endogenous brain lipid mediators with multiple mechanisms of action that are beneficial in stroke, including vasodilation, cytoprotection, anti-inflammation and suppression of platelet aggregation. Ample evidence from our group and others demonstrate that sEH inhibition and gene deletion reduce infarct size and improve functional outcomes after experimental ischemia-reperfusion injury in brain. The benefits of sEH inactivation in experimental ischemic stroke have been demonstrated in young and old male and female mice with diabetes and hypertension. Importantly, gain of function mutations in the sEH gene, called EPHX2, are associated with increased risk of ischemic stroke and worse outcome in humans, whereas carriers of a loss-of-function mutation have reduced risk of stroke and improved outcome. We have recently completed a Phase Ib clinical trial using GSK2256294 in patients with aneurysmal subarachnoid hemorrhage (SAH). The trial demonstrated that GSK2256294, administered orally for 10 days, is safe and well tolerated in critically ill patients with SAH. Although not powered for efficacy, the trial also showed trends for improvement in relevant functional outcomes. The proposed studies will test the efficacy of GSK2256294 in the NINDS Stroke Preclinical Assessment Network (SPAN) using the transient MCAO occlusion (tMCAO) model in young adult and aged mice with type 2 diabetes. PI will participate on the SPAN Steering Committee, attend all SPAN meetings and work collaboratively with all awarded sites, the Coordinating Center (CC) and NINDS Program staff to achieve the goals of the SPAN program. GSK2256294 will be synthesized by a highly experienced contract research organization (BOC Sciences) and will be provided in a sufficient amount to be tested in parallel by the entire SPAN network. PI will work with the CC to validate activity, concentration and solubility of GSK2256294 and test its efficacy in the tMCAO model in a randomized and blinded fashion. The long-term goal is to support the use of GSK2256294 in a clinical trial for acute ischemic stroke (AIS) and advance its use in AIS patients. Because GSK2256294 is already approved by the FDA and has an established safety record in humans including in hemorrhagic stroke patients, it can be advanced rapidly for testing in clinical trials of AIS if efficacy is confirmed through rigorous testing by the SPAN network.