Biological pacemaker from proof-of-concept to clinic

生物起搏器从概念验证到临床

• 批准号: 9247470
• 负责人: Eugenio Cingolani
• 金额: $ 70.3万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-27 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247470
• 关键词: Address; Adenovirus Vector; Affect; Age; Animal Model; Arrhythmia; Atrioventricular Block; Biodistribution; Biological Pacemakers; Bradycardia; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiac ablation; Cardiotoxicity; Catheters; Cell physiology; Cells; Cellular Morphology; Chemistry; Chest; Clinic; Clinical; Clinical Protocols; Clinical Trials; Devices; Dominant-Negative Mutation; Dose; Electronics; Engineering; Evaluation; Exercise; Family suidae; Future; Gene Expression; Gene Transfer; Genes; Goals; Heart Block; Heart Rate; Human; Infection; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Ion Channel; Life; Longitudinal Studies; Maps; Methods; Modeling; Pacemakers; Patients; Pharmacology; Physiologic Monitoring; Physiological; Population; Pre-Clinical Model; Research; Research Proposals; Safety; Sinoatrial Node; Somatic Gene Therapy; Techniques; Testing; Therapeutic Agents; Thinking; Time; Toxicology; Translating; Translations; Ventricular; Viral; base; chronotropic; clinical application; design; efficacy testing; electronic pacemaker; feeding; gene therapy; heart rate variability; heart rhythm; immune clearance; implantation; in vivo; minimally invasive; nodal myocyte; overexpression; patient population; pre-clinical; programs; research clinical testing; response; stressor; symposium; systemic toxicity; therapeutic candidate; transcription factor; vector

Project Summary The overall objective of the proposal is to lay the preclinical groundwork for first-in-human studies of biological pacemakers (BioP) as alternatives to electronic devices. 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 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. The proposal utilizes the abovementioned percutaneous delivery method to refine and validate, in a large-animal model of bradycardia, 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. We will go on to perform long-term efficacy, toxicology and biodistribution studies with the more promising therapeutic candidate, and then prepare, and obtain approval of, an Investigational New Drug (IND) application for a first-in-human BioP trial. While the ultimate goal may be to render obsolete the electronic pacemaker, it is important to be realistic in thinking about potential first-in-human applications. Therefore, we have chosen to develop, initially, a bridge-to-device product that will temporarily provide hardware-free chronotropic support in infected patients who are pacemaker-dependent. To make BioP temporary, we deliver the genes in adenoviral vectors, relying on immunological clearance to limit bioactivity. Nevertheless, we will test catheter ablation of the BioP as a backup rescue strategy in case of persistent undesired BioP activity. This research proposal is designed to lay the groundwork for clinical testing of an optimized BioP initially in a needy population.

项目摘要 该提案的总体目标是为生物学的首次人体研究奠定临床前基础。 起搏器（BioP）作为电子设备的替代品。基于基因的生物P首先被描述为超过一个 十年前;各种构建体的体细胞基因转移（内向整流子的显性负突变体） 通道[Kir2.1AAA]、野生型HCN通道和转录因子[Tbx 18]）都已被证明 创造生物活性。然而，直到最近，体内临床前应用大多限于高度- 入侵模式我们开发了一种临床上现实的微创输送技术，并将其用于 在完全心脏传导阻滞的猪模型中创建BioP。在这里，我们建议使用这种方法来比较两个 具有根本不同的作用机制的“决赛”治疗候选物。第一个是野生型的 离子通道（HCN 2），通过功能性重新激活， 工程.我们的目标不是创造一个忠实的起搏细胞复制品，而是操纵一个单一的 细胞膜通道的组成部分，以诱导在一个可兴奋的，但 正常静止细胞第二种候选治疗药物Tbx 18的活性成分重新编程 心室心肌细胞进入窦房结（SAN）样起搏细胞（诱导的SAN [iSAN]细胞）。没有人 兴奋性的决定因素是选择性过度表达：整个基因表达程序被改变， 导致基本细胞生理学和形态学的变化。该提案利用了上述 在心动过缓的大型动物模型中， 需要翻译到诊所。我们将描述和比较HCN 2的起搏有效性和安全性 和Tbx 18衍生的BioP，检验iSAN细胞将提供上级变时性支持的假设， 与HCN 2相比。我们将继续进行长期疗效，毒理学和生物分布研究， 更有前途的治疗候选药物，然后准备并获得研究新药的批准 (IND)申请首次人体生物磷试验虽然最终的目标可能是使过时的， 电子起搏器，重要的是要现实地考虑潜在的首次在人体中的应用。 因此，我们最初选择开发一种桥接到设备的产品， 起搏器依赖性感染患者的无硬件变时性支持。制作BioP 暂时，我们将基因递送到腺病毒载体中，依靠免疫清除来限制生物活性。 尽管如此，我们将测试BioP的导管消融，作为持续性情况下的备用抢救策略。 不希望的BioP活性。这项研究计划旨在为临床试验奠定基础， 优化BioP最初在贫困人口中。