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.

项目摘要 拟议的转化研究将确定GSK 2256294的脑保护功效，GSK 2256294是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， 底物环氧二十碳三烯酸（ESTs），其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。来自我们小组和其他人的充分证据表明，sEH抑制和基因 删除可减少实验性缺血再灌注损伤后的梗死面积并改善功能结局 个脑袋sEH失活在实验性缺血性卒中中的益处已经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中功能突变的获得 EPHX 2基因与人类缺血性中风风险增加和预后恶化有关， 而功能丧失突变的携带者中风的风险降低，结果改善。我们有 最近完成了一项在蛛网膜下腔出血患者中使用GSK 2256294的Ib期临床试验 出血（SAH）。该试验表明，口服GSK 2256294 10天是安全的， 在SAH重症患者中耐受。虽然没有效力，但试验也显示了以下趋势： 相关功能成果的改善。拟议的研究将测试GSK 2256294在以下患者中的疗效： NINDS卒中临床前评估网络（SPAN）使用短暂性MCAO闭塞（tMCAO）模型， 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，参加所有 SPAN与所有获奖站点、协调中心（CC）和NINDS举行会议并开展协作 计划工作人员实现SPAN计划的目标。GSK 2256294将由一个高度 经验丰富的合同研究组织（中银科学），并将提供足够的金额， 在整个SPAN网络中进行并行测试。PI将与CC合作，以验证活性、浓度和 本发明的目的是通过测定GSK 2256294的溶解度，并以随机化和盲法方式在tMCAO模型中测试其功效。的 长期目标是支持GSK 2256294在急性缺血性卒中（AIS）临床试验中的使用，并推进 在AIS患者中的应用因为GSK 2256294已经被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的记录，它可以迅速推进临床试验的测试 如果疗效通过SPAN网络的严格测试得到证实，