A New and Disruptive Gene Based Therapy for Atrial Fibrillation

项目摘要 心房颤动（AF）是最常见的心律失常，影响超过300万美国人，是一种严重的心脏病。 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，目前的房颤治疗方法--包括药物和消融-- 在持续性房颤患者中， 靶向导致AF的基本分子信号通路。在这个快速通道SBIR提案中， Therapeutics，Inc（RTI）提出了一种针对主要分子机制的完全不同的AF方法 使用西北大学授权的技术，RTI提出了一种创新的基因， 靶向氧化损伤的治疗策略，这是一种基本的“上游”生物机制， 控制关键的“下游”信号通路，有助于AF的电和结构重塑。 RTI策略技术创新是双重的：i）使用NOX 2 shRNA抑制NOX 2，一种主要的酶， 心房中氧化损伤的来源和ii）一种新的经静脉基因递送方法， 通过使用电穿孔进行内源性基因递送;为此目的，我们将使用导管（FirMap，Abbott-St. Jude），目前已获批用于AF的电生理标测。 RTI的首要目标是开发一种新的机制指导的房颤治疗方法， 在持续性房颤患者中， 研究性新药（IND）使RTI的组合产品的临床前研究成为可能。的假设 该II期SBIR的基础是“通过经静脉途径电穿孔介导的NOX 2 shRNA递送： a）以线性、剂量依赖性方式减弱AF中的电/结构重构，和B）具有有利的 安全配置文件”。在第一阶段，具体目标1，RTI将确定最佳的电穿孔参数，用于trans-DNA的转化。 使用FirMap导管进行静脉心房基因递送。在第二阶段，具体目标1，我们将确定 在AF心力衰竭模型中预防心房纤维化的NOX 2 shRNA的最佳治疗剂量。 II，具体目标2，我们将确定：a）逆转N 0X 2 shRNA的最佳治疗剂量， 在AF的快速心房起搏模型中建立的电重构和B）NOX 2的功效的持续时间 在相同的AF模型中逆转AF的shRNA。在第二阶段，具体目标3，RTI将进行关键毒理学 和生物分布研究。AF是一个超过20亿美元的市场。RTI的治疗 这种方法如果成功，预计将大大改善目前的药理学和生物学方法的成功。 房颤消融策略，从而导致房颤管理的范式转变。

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.