Preclinical development of biological pacemakers

生物起搏器的临床前开发

• 批准号: 10231051
• 负责人: James F. Dawkins
• 金额: $ 13.52万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231051
• 关键词: Affect; Age; Animal Model; Arrhythmia; Atrioventricular Block; Attenuated; Autonomic nervous system; Biological Pacemakers; Biological Testing; Bradyarrhythmias; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catheters; Cell physiology; Cells; Cellular Morphology; Chest; Chronic; Clinic; Clinical; Data; Devices; Dominant-Negative Mutation; Electronics; Engineering; Evaluation; Family suidae; Functional disorder; Gene Expression; Genes; Goals; Heart Block; Heart Rate; Heart failure; Implant; Infection; Injections; Ion Channel; Lead; Left; Left Ventricular Function; Magnetic Resonance Imaging; Maps; Measures; Mental Depression; Mentors; Methods; Modeling; Molecular; Outcome; Patients; Pharmacology; Physical activity; Physiological; Placebos; Population; Pre-Clinical Model; Research Proposals; Risk; Safety; Sinoatrial Node; Site; Somatic Gene Therapy; System; Techniques; Testing; Therapeutic Agents; Time; Translations; Ventricular; Ventricular Remodeling; base; chronotropic; circadian; design; electronic pacemaker; first-in-human; heart function; heart rate monitor; heart rate variability; heart rhythm; implantation; in vivo; minimally invasive; nodal myocyte; overexpression; porcine model; pre-clinical; preclinical development; prevent; programs; response; stressor; therapeutic candidate; transcription factor

Abstract: Chronic right ventricular (RV) pacing can cause RV pacing-induced cardiomyopathy (RPVIC). Approximately 20% of patients paced from the RV apex develop RVPIC, with a dramatic depression of systolic function. Symptomatic heart failure is not infrequent, and long-term outcomes are poor. Clearly, alternatives to RV pacing are desirable, but there are no validated preclinical models of RVPIC to help understand mechanisms and to guide therapy. Here we seek to validate a non-tachycardic pacing model of RVPIC in a porcine model of complete heart block, and to use this model to test biological pacemakers (BioP). Gene-based BioP were first described more than a decade ago; somatic gene transfer of various constructs (a dominant-negative mutant of the inward rectifier channel [Kir2.1AAA], wild-type HCN channels, and a transcription factor [Tbx18]) have all been shown to create BioP activity. However, until recently, in vivo preclinical applications have been mostly limited to highly-invasive open-chest models. We have developed a clinically-realistic minimally-invasive delivery technique and used it to create BioP in a porcine model of complete heart block. Here, we propose to use this approach to compare two “finalist” therapeutic candidates with fundamentally different mechanisms of action. The first one is a wild-type ion channel (HCN2) that artificially induces automaticity in ventricular cardiomyocytes by functional re-engineering. The goal is not to create a faithful replica of a pacemaker cell, but rather to manipulate a single component of the membrane channel repertoire so as to induce spontaneous firing in an excitable but normally-quiescent cell. The active principle of the second therapeutic candidate, Tbx18, reprograms ventricular cardiomyocytes into sinoatrial node (SAN)-like pacemaker cells (induced SAN [iSAN] cells). No one determinant of excitability is selectively over-expressed: the entire gene expression program is altered, with resultant changes in fundamental cell physiology and morphology. This proposal utilizes the above mentioned percutaneous delivery method to reduce to refine and validate, in a large-animal model of RVPIC, the approaches required for translation to the clinic. We will characterize and compare the pacing efficacy and safety of HCN2 and Tbx18-derived BioP, testing the hypothesis that iSAN cells will provide superior chronotropic support as compared to HCN2. Once designating the most promising therapeutic candidate, we will then test the utility of BioP in the setting of RVPIC. We hypothesize that restoring antegrade conduction by his-bundle pacing with a BioP can attenuate or reverse the adverse ventricular remodeling associated with right ventricular pacing. This research proposal is designed to lay the pre-clinical groundwork for testing of an optimized BioP in patients at risk for RVPIC.

摘要：慢性右心（RV）起搏会导致RV起搏引起的心肌病（RPVIC）。 大约20％的患者从RV Apex发育开发RVPIC的患者中，收缩期很大 功能。有症状的心力衰竭并不是很少的，并且长期结局很差。显然，替代方案 RV起搏是可取的，但是没有经过验证的RVPIC临床前模型来帮助了解机制 并指导治疗。在这里，我们试图在猪的猪模型中验证RVPIC的非电视节奏模型 完整的心脏障碍，并使用此模型测试生物起搏器（Biop）。基于基因的Biop是第一个 描述了十多年前；各种构建体的体细胞基因转移（一种显性阴性突变体 内向整流器通道[KIR2.1AAA]，野生型HCN通道和转录因子[TBX18]） 被证明会产生生物活动。但是，直到最近，体内临床前应用主要是 仅限于高度侵入性的开胸模型。我们已经开发了一种临床现实的微创输送 技术并用它在完整心脏块的猪模型中创建了Biop。在这里，我们建议使用这个 将两个“决赛”治疗候选者与基本不同的作用机理进行比较的方法。 第一个是野生型离子通道（HCN2），该通道人为地诱导心室心肌细胞自动化 通过功能重新设计。目的不是创建起搏器单元的忠实复制品，而是要 操纵膜通道曲目的单个组成部分 令人兴奋但通常是频率的细胞。第二个治疗候选者TBX18的主动原理， 将心室心肌细胞重新编程到窦节点（SAN）类似起搏器细胞（诱导的SAN [ISAN] 细胞）。没有一个兴奋的决定者选择性地表达了：整个基因表达程序是 改变了，导致基本细胞生理和形态的变化。该建议利用了上述 提到的经皮递送方法是在大型的RVPIC模型中简化和验证 转化为诊所所需的方法。我们将表征和比较起搏效率，并且 HCN2和TBX18衍生的Biop的安全性，检验了Isan细胞将提供高表现的假设 与HCN2相比。一旦设计了最有前途的治疗候选者，我们将测试 Biop在RVPIC环境中的实用程序。我们假设通过His-Bundle恢复前进的传导 用Biop起搏可以减弱或逆转与右心室相关的不良心室重塑 起搏。该研究建议旨在为测试优化的Biop的临床前基础工作奠定 有RVPIC风险的患者。