Translating post-infarct ventricular tachycardia mechanisms into a therapy

将梗死后室性心动过速机制转化为治疗方法

• 批准号: 10608264
• 负责人: J Kevin Donahue
• 金额: $ 82.38万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-09 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608264
• 关键词: Abbreviations; Action Potentials; Anatomy; Area; Arrhythmia; Atrial Fibrillation; Attenuated; Autopsy; Biodistribution; Cause of Death; Cell physiology; Cessation of life; Cicatrix; Complex; Connexin 43; Coronary Arteriosclerosis; Data; Dependovirus; Developed Countries; Disease; Ectopic beats; Electrophysiology (science); Elements; Environment; Etiology; Event; Fiber; Functional disorder; Future; Gap Junctions; Gene Delivery; Gene Transfer; Genes; Goals; Green Fluorescent Proteins; Heart Arrest; Heart Atrium; Heterogeneity; Impairment; Infarction; Intercalated disc; Intervention; Investigational New Drug Application; Left Ventricular Ejection Fraction; Malignant - descriptor; Methods; Monitor; Muscle Cells; Mutation; Myocardial; Myocardial Infarction; Myocardial tissue; Paint; Patients; Pattern; Perfusion; Persons; Postoperative Period; Potassium Channel; Program Development; Proteins; Refractory; Reporting; Research; Role; Safety; Serious Adverse Event; Sudden Death; Tachyarrhythmias; Testing; Time; Tissues; Transgenes; Translating; United States; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; Work; adeno-associated viral vector; clinical development; efficacy evaluation; experience; gene therapy; gene therapy clinical trial; healing; novel; pre-clinical; pre-clinical therapy; prevent; research clinical testing; response; sudden cardiac death; therapy development; transgene delivery

ABSTRACT In the United States, several hundred thousand people experience cardiac arrest each year, with the vast majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a myocardial infarction (MI), and death results from maladaptive responses to infarct healing. The healed infarct scar creates a substrate that supports malignant ventricular arrhythmias, and death results from ventricular tachycardia (VT) originating in the border zone around the infarct scar. The prevailing paradigm focused on the role of surviving ribbons of myocardial tissue traversing the borderzone region and impaired electrical conduction as components of the arrhythmia mechanism. A problem with ascribing causation of VT entirely to those electrical conduction factors is that they occur diffusely throughout the borderzone, but VT exists in discrete circuits. We recently reported that the potassium channel beta subunits KCNE3 and KCNE4 are upregulated only in VT circuits, and that these proteins cause a pattern of repolarization heterogeneity that supports reentrant VT. We have also shown that gene transfer of either repolarization prolonging or conduction enhancing transgenes reduces or eliminates VT inducibility. We previously developed an epicardial gene painting method for transmural atrial gene transfer, and we have preliminary data showing that use of epicardial gene painting with adeno-associated virus vectors allows complete transmural ventricular gene transfer. In this proposal, we exploit these findings to develop a cure for post-infarct VT. We hypothesize that the VT circuit-specific repolarization effects combine with the more broadly present alterations in conduction to create an environment conducive for reentry VT, and that normalizing repolarization and/or conduction will prevent VT. To test our hypothesis, we will focus on 3 aims: (1) to homogenize repolarization in healed MI scar; (2) to normalize conduction velocity and cellular connectivity by increasing intercalated disk expression of connexin43; (3) to evaluate safety and biodistribution of the proposed interventions. Successful completion of these aims will create a preclinical data package required to support future clinical testing of VT gene therapy.

摘要 在美国，每年有数十万人经历心脏骤停， 大多数人死于这种情况。大约三分之二的心脏骤停受害者以前曾遭受 心肌梗塞（MI），以及对梗塞愈合的适应不良反应导致的死亡。愈合的梗塞 瘢痕形成支持恶性室性心律失常的基质， 起源于梗塞瘢痕周围边缘区的心动过速（VT）。流行的范例集中在 存活的心肌组织带穿过边界区和受损的电 传导作为心律失常机制的组成部分。将VT的原因完全归因于 这些电传导因素是，它们在整个边界区扩散发生，但VT存在于 离散电路我们最近报道，钾通道β亚基KCNE 3和KCNE 4是 仅在VT回路中上调，并且这些蛋白质引起复极异质性模式， 支持折返VT。我们还表明，无论是复极延长或传导的基因转移， 增强转基因减少或消除VT诱导。我们之前开发了一种心外膜基因 我们有初步的数据表明，使用 腺相关病毒载体的心外膜基因涂敷允许完全透壁心室基因 转移在这个建议中，我们利用这些发现来开发一种治疗梗死后VT的方法。我们假设 VT回路特异性复极化效应联合收割机与更广泛存在的传导改变相结合， 创造一个有利于折返VT的环境，并且正常化复极和/或传导将 预防VT。为了验证我们的假设，我们将集中在3个目标：（1）均匀复极愈合的MI 瘢痕;（2）通过增加闰盘表达，使传导速度和细胞连接正常化， connexin 43;（3）评价所提出的干预措施的安全性和生物分布。成功完成 这些目标将创建支持VT基因疗法的未来临床测试所需的临床前数据包。