Identification of mechanism-based therapies to treat arrhythmogenic cardiomyopathy by resolving perturbations in regulatory lipid signaling

通过解决调节脂质信号传导的扰动来鉴定治疗心律失常性心肌病的基于机制的疗法

• 批准号: 10484571
• 负责人: Irene Cortes-Puch
• 金额: $ 27.91万
• 依托单位: EICOSIS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484571
• 关键词: Acute; Address; Affect; Analgesics; Animal Model; Anti-Inflammatory Agents; Applications Grants; Arachidonic Acids; Arrhythmia; Autopsy; Biological; Cardiac; Cardiac Myocytes; Categories; Chronic; Clinical; Clinical Trials; Cytochrome P450; Data; Desmosomes; Disease; Disease Progression; Dose; Drug Kinetics; Eicosanoids; Electrocardiogram; Enzymes; Epoxide hydrolase; Equilibrium; Family; Fatty Acids; Future; Glycols; Goals; Heart; Heart Diseases; Heart Rate; Heart failure; Heritability; Holter Electrocardiography; Human; Implantable Defibrillators; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Life; Lipids; Mediator of activation protein; Metabolism; Muscle; Mutation; Natural History; Oral; Patients; Persons; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase Ib Clinical Trial; Pilot Projects; Placebos; Polyunsaturated Fatty Acids; Process; Production; Prognosis; Property; Quality of life; Regimen; Resolution; Risk; Role; Safety; Sampling; Series; Signal Transduction; Small Business Innovation Research Grant; Solid; Sudden Death; Testing; Therapeutic; Time; Tissues; Ventricular; Ventricular Arrhythmia; arrhythmogenic cardiomyopathy; base; burden of illness; cardiac muscle disease; cytokine; drug candidate; healthy volunteer; improved; induced pluripotent stem cell; inhibitor; lipid mediator; palliative; prevent; small molecule; sudden cardiac death; therapeutic target

Abstract The goal of this SBIR Phase I proposal is to demonstrate safety and provide a solid rationale for targeting eicosanoid-driven inflammation through inhibition of the soluble epoxide hydrolase (sEH) enzyme in patients with arrhythmogenic cardiomyopathy (ACM). ACM is a heritable heart-muscle disease caused by a genetic defect in cardiac desmosomes, resulting in the progressive loss of ventricular muscle and its replacement by fibrofatty tissue. ACM affects 1 in 5000 persons and is clinically characterized by life-threatening ventricular arrhythmias and progression to debilitating heart failure. It is a common cause of sudden death in young people, especially athletes. Current therapies are mostly palliative, focused on preventing sudden death with implantable cardioverter defibrillators. There is an unmet need for mechanism-based therapies that can modify disease progression and improve quality of life of ACM patients. Substantial evidence shows inflammation is a key feature of ACM disease progression, suggesting ACM represents a chronic inflammatory condition and opening the possibility to alter its natural history with targeted anti-inflammatory therapies. Recent data demonstrate that bioactive lipid mediators formed from the metabolism of polyunsaturated fatty acids (PUFA) can resolve inflammation through a balance of anti- and pro-inflammatory lipid mediators, known as eicosanoids. PUFA-derived epoxy fatty acids (EpFA) are formed by CYP450s and have potent inflammation-resolving properties. However, their beneficial effects are limited by their rapid metabolism into inactive or even pro-inflammatory diols by the sEH enzyme. Notably, these pro-inflammatory diols are significantly increased in patients with ACM, suggesting a potential therapeutic role of inhibiting sEH to restore the balance between EpFA and their diols. EicOsis has developed a small-molecule oral inhibitor of the sEH enzyme, EC5026, and is currently conducting Phase 1 clinical trials in humans. Here, we propose to determine the cardiac safety profile of EC5026 and provide additional scientific rationale for targeting eicosanoid-driven inflammation in patients with ACM through sEH inhibition. We will attain these goals by: 1) determining the cardiac safety profile of oral EC5026 analyzing previously collected continuous electrocardiogram data from an ongoing Phase 1b multiple ascending dose study in healthy volunteers; 2) characterizing the baseline alterations of eicosanoids and other inflammatory mediators in ACM patients and compare it to non-affected family matched controls; and, 3) evaluating the effects of EC5026 in human induced pluripotent stem cells (hiPSC) cardiac myocytes derived from patients with ACM. We expect to demonstrate that inhibiting the sEH enzyme with oral EC5026 is a safe therapeutic approach with the potential of successfully modifying the underlying inflammatory component of ACM, providing a strong rationale to seek a Phase II SBIR application to conduct a pilot clinical trial of EC5026 in patients with ACM.

抽象的 SBIR 第一阶段提案的目标是证明安全性并为目标提供坚实的理由 通过抑制患者的可溶性环氧化物水解酶（sEH），类二十烷酸驱动的炎症 致心律失常性心肌病（ACM）。 ACM 是一种遗传性心肌疾病，由遗传缺陷引起 心脏桥粒，导致心室肌逐渐丧失并被纤维脂肪替代 组织。 ACM 影响五千分之一的人，临床特征是危及生命的室性心律失常 并进展为衰弱性心力衰竭。这是年轻人猝死的常见原因，尤其是 运动员。目前的疗法大多是姑息治疗，重点是通过植入物预防猝死 心脏复律除颤器。对能够改变疾病的基于机制的疗法的需求尚未得到满足 进展并提高 ACM 患者的生活质量。 大量证据表明炎症是 ACM 疾病进展的关键特征，提示 ACM 代表一种慢性炎症状况，并开启了有针对性地改变其自然史的可能性 抗炎治疗。最近的数据表明，生物活性脂质介质是由代谢形成的 多不饱和脂肪酸（PUFA）可以通过抗炎和促炎的平衡来解决炎症 脂质介质，称为类二十烷酸。 PUFA 衍生的环氧脂肪酸 (EpFA) 由 CYP450 和 具有有效的消炎特性。然而，它们的有益效果因其快速性而受到限制。 通过 sEH 酶代谢为无活性甚至促炎二醇。值得注意的是，这些促炎 ACM 患者中二醇显着增加，表明抑制 sEH 具有潜在的治疗作用 恢复 EpFA 及其二醇之间的平衡。 EicOsis 开发了一种小分子口服抑制剂 sEH酶，EC5026，目前正在进行人体1期临床试验。 在这里，我们建议确定 EC5026 的心脏安全性并提供额外的科学依据 通过 sEH 抑制来针对 ACM 患者中类二十烷酸驱动的炎症。我们将实现这些目标 通过：1) 分析先前连续收集的口服 EC5026 来确定心脏安全性概况 来自正在进行的健康志愿者 1b 期多次递增剂量研究的心电图数据； 2） 描述 ACM 患者中类二十烷酸和其他炎症介质的基线变化， 将其与未受影响的家庭匹配对照进行比较；以及，3) 评估 EC5026 对人类诱导的效果 来自 ACM 患者的多能干细胞 (hiPSC) 心肌细胞。我们希望证明 用口服 EC5026 抑制 sEH 酶是一种安全的治疗方法，具有成功的潜力 改变 ACM 的潜在炎症成分，为寻求 II 期 SBIR 提供强有力的理由 申请在 ACM 患者中进行 EC5026 的初步临床试验。