Soluble Epoxide Hydrolase Inhibitor GSK2256294 for Acute Ischemic Stroke

可溶性环氧化物水解酶抑制剂 GSK2256294 用于治疗急性缺血性中风

• 批准号: 10672750
• 负责人: Nabil J Alkayed
• 金额: $ 34.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672750
• 关键词: Acute; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Arachidonic Acids; Award; Blinded; Brain; Brain Injuries; Brain hemorrhage; Cerebral Ischemia; Clinical Trials; Critical Illness; Cytochrome P450; Cytoprotection; Diabetes Mellitus; Dose; Eicosanoids; Enzymes; Epoxide hydrolase; Experimental Designs; FDA approved; Female; Gene Deletion; Goals; Human; Hydrolase; Hypertension; Infarction; Inflammation; Ischemic Brain Injury; Ischemic Stroke; Lipoxygenase; Membrane; Metabolism; Middle Cerebral Artery Occlusion; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Non-Insulin-Dependent Diabetes Mellitus; Oral Administration; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase Ib Clinical Trial; Phospholipids; Physiological; Platelet aggregation; Play; Progress Reports; Prostaglandin-Endoperoxide Synthase; Protocols documentation; Publications; Randomized; Reperfusion Injury; Research Contracts; Risk; Rodent; Role; Safety; Science; Signaling Molecule; Site; Solubility; Stroke; Subarachnoid Hemorrhage; Testing; Therapeutic; Update; Validation; Vasodilation; Work; aged; diabetic; efficacy testing; efficacy validation; experience; functional improvement; functional outcomes; gain of function mutation; genetic association; improved; improved outcome; in vivo; inhibitor; lipid mediator; loss of function mutation; male; meeting abstracts; meetings; non-diabetic; post stroke; pre-clinical assessment; programs; stroke model; stroke outcome; stroke patient; stroke risk; timeline; translational study; trend; young adult

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.

项目概要 拟议的转化研究将确定 GSK2256294（FDA 批准的药物）的脑保护功效。 批准的可溶性环氧化物水解酶 (sEH) 抑制剂。抑制 sEH 会增加其内源性水平 底物环氧二十碳三烯酸酯 (EET)，是具有多种机制的内源性脑脂质介质 对中风有益的作用，包括血管舒张、细胞保护、抗炎和抑制 血小板聚集。我们小组和其他人的充足证据表明 sEH 抑制和基因 缺失可减少梗死面积并改善实验性缺血再灌注损伤后的功能结果 脑。 sEH 失活对实验性缺血性中风的益处已在年轻人和老年人中得到证实。 患有糖尿病和高血压的老年雄性和雌性小鼠。重要的是，sEH 中的功能突变 称为 EPHX2 的基因与人类缺血性中风风险增加和预后较差相关， 而功能丧失突变的携带者则降低了中风风险并改善了预后。我们有 最近完成了一项使用GSK2256294治疗动脉瘤性蛛网膜下腔患者的Ib期临床试验 出血（SAH）。试验表明，口服 10 天的 GSK2256294 是安全且效果良好的 SAH 危重患者可耐受。尽管没有提供功效，但该试验也显示了以下趋势： 相关功能结果的改善。拟议的研究将测试 GSK2256294 在 NINDS 中风临床前评估网络 (SPAN) 使用瞬时 MCAO 闭塞 (tMCAO) 模型 患有 2 型糖尿病的年轻成年和老年小鼠。 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 计划人员实现 SPAN 计划的目标。 GSK2256294将由高度合成 经验丰富的合同研究组织（BOC Sciences），并将提供足够的金额 由整个 SPAN 网络并行测试。 PI 将与 CC 合作验证活动、浓度和 GSK2256294 的溶解度，并以随机和盲法方式测试其在 tMCAO 模型中的功效。这 长期目标是支持GSK2256294在急性缺血性中风（AIS）的临床试验中的使用并推进 它在 AIS 患者中的应用。因为GSK2256294已经获得FDA批准并且具有既定的安全性 在人类（包括出血性中风患者）中取得记录，可以快速推进临床试验测试 如果通过 SPAN 网络的严格测试确认了 AIS 的有效性。