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 I期建议的目的是证明安全性并为目标提供坚实的理由 通过抑制可溶性环氧化物水解酶（SEH）酶的eicosanoid驱动的炎症 心律不齐的心肌病（ACM）。 ACM是由遗传缺陷引起的一种可遗传的心肌疾病 心脏脱粒体，导致心室肌肉的逐渐丧失及其用纤维纤维替代 组织。 ACM影响5000人中的1人，并在临床上以威胁生命的心律不齐为特征 和使人衰弱的心力衰竭。这是年轻人突然死亡的常见原因，尤其是 运动员。当前的疗法主要是姑息治疗，专注于防止植入的猝死 心脏扭曲器除颤器。对基于机制的疗法的需求未满足，可以改变疾病 进展并改善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，表明ACM 代表一种慢性炎症状况，并开放了改变其自然历史的可能性 抗炎疗法。最近的数据表明，由代谢形成的生物活性脂质介质 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，称为类类。 PUFA来源的环氧脂肪酸（EPFA）由CYP450形成，并形成 具有有效的炎症特性。但是，它们的有益效果受其快速的限制 SEH酶为非活性甚至促炎性二醇的代谢。值得注意的是，这些促炎 ACM患者的二醇显着增加，表明抑制SEH的潜在治疗作用 恢复EPFA与其二醇之间的平衡。 Eicosis已开发出一种小分子的口服抑制剂 SEH酶，EC5026，目前正在人类进行1期临床试验。 在这里，我们建议确定EC5026的心脏安全性，并为 通过SEH抑制，ACM患者靶向eicosanoid驱动的炎症。我们将实现这些目标 作者：1）确定口服EC5026的心脏安全性，分析先前收集的连续收集 在健康志愿者中，正在进行的1B阶段多升剂量研究的心电图数据； 2） 表征ACM患者和 将其与未受影响的家族匹配的控件进行比较； 3）评估EC5026对人类诱导的影响 源自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 修改ACM的潜在炎症成分，提供了强大的理由来寻求II期SBIR 在ACM患者中进行EC5026的试验临床试验的应用。