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

基本信息

批准号：
10563221
负责人：
Robert Charles Moen
金额：
$ 174.99万
依托单位：
INOMAGEN THERAPEUTICS, INC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10563221
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 Licensing Luciferases Maps Marketing Maximum Tolerated Dose Mediating Methods Modeling Molecular Molecular Target Morbidity - disease rate Muscle Cells NADPH Oxidase Outcome Patients Persons Pharmaceutical Preparations Phase Plasmids Procedures Process Pulmonary veins Refractory Research Resistance Risk Role Route Safety Saint Jude Children&apos s Research Hospital Signal Pathway Small Business Innovation Research Grant Source Stroke Techniques Technology Testing Therapeutic Time Toxic effect Toxicology Transfection Transgenes Universities Veins Venous Work age related aging population autonomic nerve commercial application cost gene therapy heart rhythm high risk improved innovation mortality novel novel therapeutic intervention oxidative damage pharmacologic plasmid DNA preclinical study prevent public health relevance response small hairpin RNA stroke risk success technological innovation therapeutic target

项目摘要

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.

项目概要心房颤动 (AF) 是最常见的心律失常，影响超过 300 万美国人，是一种由于房颤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。不幸的是，目前的房颤治疗方法——药物和消融—— 基于 - 对于持续性房颤患者来说效果不佳，这被认为是因为目前的治疗方法并不能达到最佳效果。在此 Fast-Track SBIR 提案中，Rhythm 旨在针对导致 AF 的基本分子信号传导途径。 Therapeutics, Inc (RTI) 提出了一种截然不同的治疗 AF 的方法，该方法针对主要分子机制 RTI 使用西北大学许可的技术提出了一种创新基因。针对氧化损伤的治疗策略，这是一种基本的“上游”生物机制控制有助于 AF 电气和结构重塑的关键“下游”信号通路。 RTI策略的技术创新有两个方面：i)使用NOX2 shRNA来抑制NOX2，一种主要的酶心房氧化损伤的来源和 ii) 一种新的经静脉基因传递方法，可促进使用电穿孔进行心内膜基因递送；为此，我们将使用导管（FirMap，Abbott-St. Jude）目前已被批准用于 AF 的电生理图绘制。 RTI 的首要目标是开发一种新的机制引导的 AF 治疗方法，其疗效至少提高 25% 对持续性 AF 患者的疗效优于消融该快速通道 SBIR 的目标是执行研究性新药 (IND) 能够利用 RTI 的组合产品进行临床前研究。 II 期 SBIR 的基础是“电穿孔介导的 NOX2 shRNA 通过经静脉途径的递送”： a) 以线性、剂量依赖性方式减弱电/结构重塑，并且 b) 具有良好的效果在第一阶段的具体目标 1 中，RTI 将确定反转录的最佳电穿孔参数。使用 FirMap 导管进行静脉心房基因递送在第二阶段的具体目标 1 中，我们将确定 NOX2 shRNA 的最佳治疗剂量可预防 AF 心力衰竭模型中的心房纤维化。 II，具体目标2，我们将确定：a）逆转NOX2 shRNA的最佳治疗剂量在 AF 的快速心房起搏模型中建立了电重构，并且 b) NOX2 的疗效持续时间 shRNA 在同一 AF 模型中逆转 AF 的作用在第二阶段的具体目标 3 中，RTI 将进行关键的毒理学研究。及其组合产品的生物分布研究是 RTI 的一个价值超过 20 亿美元的市场。如果成功，预计该方法将显着改善当前药理学和 AF 的消融策略，从而导致 AF 管理的范式转变。