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.

摘要 本SBIR I期提案的目标是证明安全性并为靶向提供坚实的理由 通过抑制可溶性环氧化物水解酶（sEH），类花生酸驱动的炎症 致心肌病（ACM）。ACM是一种遗传性心脏肌肉疾病， 心脏桥粒，导致心室肌逐渐丧失并被纤维脂肪取代 组织. ACM影响1/5000人，临床特征为危及生命的室性心律失常 并发展为心力衰竭这是年轻人猝死的常见原因，尤其是 运动员目前的治疗大多是姑息性的，重点是预防猝死， 心律转复器对于可以改变疾病的基于机制的疗法存在未满足的需求 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 代表一种慢性炎症性疾病，并打开了改变其自然史的可能性， 抗炎治疗。最近的数据表明，生物活性脂质介质形成的代谢 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CYP 450形成， 具有有效的消炎特性。然而，它们的有益效果受到其快速性的限制。 通过sEH酶代谢成无活性或甚至促炎性二醇。值得注意的是，这些促炎症 二醇在ACM患者中显著增加，表明抑制sEH对ACM的潜在治疗作用。 恢复EpFA和它们的二醇之间的平衡。EicOsis开发了一种小分子口服抑制剂， sEH酶，EC 5026，目前正在进行人体1期临床试验。 在此，我们建议确定EC 5026的心脏安全性，并提供额外的科学依据， 通过sEH抑制靶向ACM患者中类花生酸驱动的炎症。我们将实现这些目标 通过：1）通过分析先前收集的连续数据来确定口服EC 5026的心脏安全性特征， 来自健康志愿者中正在进行的Ib期多次给药剂量递增研究的心电图数据; 2） 表征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族匹配对照进行比较;以及，3）评估EC 5026在人类诱导的 多能干细胞（hiPSC）是来源于患有ACM的患者的心肌细胞。我们希望证明， 口服EC 5026抑制sEH酶是一种安全的治疗方法， 改变ACM的潜在炎症成分，为寻求II期SBIR提供了强有力的理论基础 申请在ACM患者中进行EC 5026的初步临床试验。