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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在美国，每年有数十万人经历心脏骤停，其中大多数人死于这种情况。大约三分之二的心脏骤停受害者此前曾遭受过心脏骤停心肌梗塞（MI）和死亡是由于梗塞愈合的适应不良反应引起的。已治愈的梗塞疤痕形成了支持恶性室性心律失常的基质，室性心律失常导致死亡心动过速 (VT) 起源于梗塞疤痕周围的边界区。流行的范式集中于存活的心肌组织带穿过边界区和受损的电的作用传导作为心律失常机制的组成部分。将 VT 的因果关系完全归因于的问题这些电传导因素是它们广泛发生在整个边界区域，但 VT 存在于分立电路。我们最近报道钾通道β亚基KCNE3和KCNE4是仅在 VT 回路中上调，并且这些蛋白质导致复极异质性模式支持可重入VT。我们还表明，复极化延长或传导的基因转移增强转基因可减少或消除 VT 诱导性。我们之前开发了心外膜基因跨壁心房基因转移的绘画方法，我们有初步数据表明使用使用腺相关病毒载体进行心外膜基因绘制可实现完整的跨壁心室基因转移。在本提案中，我们利用这些发现来开发治疗梗死后 VT 的方法。我们假设 VT 电路特定的复极效应与更广泛存在的传导变化相结合创造一个有利于再入 VT 的环境，并且使复极和/或传导正常化预防室速。为了检验我们的假设，我们将重点关注 3 个目标：(1) 使治愈的 MI 中的复极均质化瘢痕; (2) 通过增加闰盘表达来使传导速度和细胞连接正常化连接蛋白43; (3) 评估所提出的干预措施的安全性和生物分布。顺利完成这些目标将创建支持 VT 基因治疗未来临床测试所需的临床前数据包。