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％的从RV Apex节奏的患者发生RVPIC，系统急剧抑郁症 功能 RV起搏是设计 为了指导治疗。 完整的心脏障碍，并使用此模型测试生物起搏器（Biop）。 十多年前描述了各种构造的体细胞基因转移 内向整流器通道[KIR2.1AAA]，野生型HCN通道和转录因子[TBX18] 但是，直到最近，都会产生生物活动 仅限于高度侵入性的开胸模型。 技术并用它在完整心脏块的猪模型中创建了Biop。 将两个“决赛选手”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I野生型离子通道（HCN2）人为地诱导腹心肌心肌细胞自动化 通过功能重新设计。 操纵膜通道库的单个组成部分，以诱导自发性 可激发但正常的细胞。 重新签名将心室心肌细胞置于促源节点样的起搏器细胞（诱导的SAN [ISAN]） 细胞）。 改变，导致基本细胞生理和形态的变化。 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。 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，一旦指定了最有前途的治疗候选者 在RVPIC的环境中，Biop的效用。 使用Biop起搏可以衰减或逆转与右心右心室相关的不良心室重塑 起搏。 有RVPIC风险的患者。