A New and Disruptive Gene Based Therapy for Atrial Fibrillation

一种新的、颠覆性的基于基因的心房颤动疗法

• 批准号: 10157794
• 负责人: Robert Charles Moen
• 金额: $ 46.27万
• 依托单位: INOMAGEN THERAPEUTICS, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157794
• 关键词: Ablation; Affect; Age; American; Anti-Arrhythmia Agents; Atrial Fibrillation; Attenuated; Autonomic nervous system; Biodistribution; Biological; Biological Products; Biological Response Modifier Therapy; Canis familiaris; Cardiac; Catheters; Clinical; Clinical Research; Coronary sinus structure; Devices; Disease; Dose; Electrophysiology (science); Electroporation; Epidemic; FDA approved; Fibrosis; Gap Junctions; Gene Delivery; Gene Expression; Gene Silencing; Genes; Goals; Heart Atrium; Heart failure; Incidence; Injections; Investigational Drugs; Ion Channel; Knowledge; Lead; Legal patent; Luciferases; Maximum Tolerated Dose; Mediating; Methods; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Muscle Cells; NADPH Oxidase; Needles; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Plasmids; Procedures; Process; Pulmonary veins; Refractory; Research; Resistance; Risk; Role; Route; Safety; Saint Jude Children' s Research Hospital; Signal Pathway; Small Business Innovation Research Grant; Source; Stroke; Structure; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicology; Universities; Veins; Venous; Work; age related; aging population; autonomic nerve; base; commercial application; cost; gene therapy; heart rhythm; high risk; improved; innovation; mortality; novel; novel therapeutic intervention; oxidative damage; plasmid DNA; preclinical study; prevent; public health relevance; response; small hairpin RNA; stroke risk; success; technological innovation; therapeutic target; transgene delivery

PROJECT SUMMARY Atrial fibrillation (AF) is the most common heart rhythm disorder that affects >3 million Americans and is a major cause of stroke. Since AF is primarily an age-related disease, it is fast becoming an epidemic in a rapidly aging population. Unfortunately, current therapeutic approaches to AF – both pharmacological and ablation- based - are sub-optimal in patients with persistent AF. This is thought to be because current treatments do not target the fundamental, molecular signaling pathways that cause AF. In this Fast-Track SBIR proposal, Rhythm Therapeutics, Inc (RTI) proposes a radically different approach to AF that targets major molecular mechanisms underlying AF. Using technology licensed from Northwestern University, RTI proposes an innovative, gene therapy strategy to target oxidative injury, which is a fundamental, ‘upstream’ biological mechanism that controls key ‘downstream’ signaling pathways contributing to electrical and structural remodeling in AF. The technical innovation of RTI’s strategy is two-fold: i) use of NOX2 shRNA to inhibit NOX2, a major enzymatic source of oxidative injury in the atria and ii) a new, trans-venous method of gene delivery that facilitates endocardial gene delivery by using electroporation; for this purpose, we will use a catheter (FirMap, Abbott-St. Jude) that is currently approved for electrophysiological mapping of AF. RTI’s overarching goal is develop a new, mechanism-guided therapy for AF that has at least 25% greater efficacy than ablation in patients with persistent AF. The goal of this Fast-Track SBIR is to perform Investigational New Drug (IND) enabling pre-clinical studies with RTI’s combination product. The hypothesis underlying this Phase II SBIR is ‘Electroporation mediated delivery of NOX2 shRNA via a trans-venous route: a) attenuates electrical/structural remodeling in AF in a linear, dose-dependent fashion and b) has a favorable safety profile’. In Phase I, Specific Aim 1, RTI will determine the optimal electroporation parameters for trans- venous atrial gene delivery using the FirMap catheter. In Phase II, Specific Aim 1, we will determine the optimal therapeutic dose of NOX2 shRNA that prevents atrial fibrosis in a heart failure model of AF. In Phase II, Specific Aim 2, we will determine: a) the optimal therapeutic dose of NOX2 shRNA that reverses established electrical remodeling in a rapid atrial pacing model of AF and b) the duration of efficacy of NOX2 shRNA in reversing AF in the same AF model. In Phase II, Specific Aim 3, RTI will conduct pivotal toxicology and bio-distribution studies with its combination product. AF is a $2 billion + market. RTI’s therapeutic approach, if successful, is expected to significantly improve upon the success of current pharmacological and ablation strategies for AF, and thereby lead to a paradigm shift in management of AF.

项目摘要 心房颤动（AF）是影响300万美国人的最常见心律障碍，是一个 中风的主要原因。由于AF主要是一种与年龄相关的疾病，因此它正在迅速成为一种流行病 人口老龄化。不幸的是，当前对AF的治疗方法 - 药物和消融 - 基于持续性AF的患者，基于优势。这被认为是因为目前的治疗没有 靶向导致AF的基本分子信号通路。在这个快速的SBIR提案中，节奏 Therapeutics，Inc（RTI）提出了针对主要分子机制的完全不同的AF方法 基础AF。 RTI使用来自西北大学许可的技术，提出了创新的基因 靶向氧化损伤的治疗策略，这是一种基本的“上游”生物学机制 控制关键的“下游”信号通路，导致AF中的电气和结构重塑。这 RTI策略的技术创新是两个方面：i）使用NOX2 SHRNA抑制NOX2，这是一种主要的酶促 心房中的氧化损伤来源和ii）一种促进基因递送的新型基因递送方法 使用电穿孔递送心内膜基因；为此，我们将使用导管（Firmap，Abbott-St。 裘德）目前已批准用于AF的电生理图。 RTI的总体目标是为AF开发一种新的机制引导疗法，该疗法至少增加了25％ 在持续性房颤的患者中的疗效而不是消融。这个快速轨道SBIR的目标是执行 研究新药（IND）可以使用RTI的组合产品实现临床前研究。假设 这一II期SBIR的基础是“通过跨性别途径的电穿孔介导的NOX2 shRNA的传递： a）以线性，剂量依赖性的方式减弱AF的电气/结构重塑，b）有利 安全概况”。在第一阶段，特定的目标1，RTI将确定反式的最佳电穿孔参数 使用Firmap导管递送静脉心房基因。在第二阶段，特定目标1中，我们将确定 NOX2 SHRNA的最佳治疗剂量可防止AF心力衰竭模型中心房纤维化。在阶段 ii，特定目标2，我们将确定：a）逆转的NOX2 shRNA的最佳治疗剂量 在AF和b的快速心房起搏模型中建立的电气化重塑）NOX2的效率持续时间 在相同的AF模型中逆转AF的shRNA。在第二阶段，特定的目标3，RTI将进行关键毒理学 以及与其组合产品的生物分布研究。 AF是一个耗资20亿美元的市场。 RTI的疗法 如果成功的话，预计将显着改善当前药理和 AF的消融策略，从而导致AF管理的范式转移。