A New and Disruptive Gene Based Therapy for Atrial Fibrillation

项目总结 房颤是影响300万美国人的最常见的心律失常，是一种 中风的主要原因。由于房颤主要是一种与年龄相关的疾病，它正在迅速成为一种流行病 人口老龄化。不幸的是，目前治疗房颤的方法--包括药物治疗和消融-- 在持续性房颤患者中，BASE-是次佳的。这被认为是因为目前的治疗方法不能 针对导致房颤的基本分子信号通路。在这份快速跟踪SBIR提案中，Rhythm Treateutics，Inc.(RTI)提出了一种针对主要分子机制的治疗房颤的根本不同的方法 潜在的房颤。利用西北大学授权的技术，RTI提出了一种创新的基因 以氧化损伤为靶点的治疗策略，这是一种基本的上游生物机制， 控制关键的“下游”信号通路，有助于房颤的电和结构重构。这个 RTI战略的技术创新有两个方面：i)使用NOX2 shRNA抑制NOX2，一种主要的酶 心房氧化损伤的来源和II)一种新的经静脉传递基因的方法，有助于 为此，我们将使用导管(FirMap，雅培-圣彼得堡)。 Jude)，目前被批准用于房颤的电生理标测。 RTI的首要目标是开发一种新的、机制导向的房颤治疗方法，其疗效至少提高25% 持续性房颤患者的疗效优于消融。此Fast-Track SBIR的目标是 研究性新药(IND)使RTI的组合产品能够进行临床前研究。假说 在这个第二阶段SBIR的基础上，电穿孔通过静脉途径传递NOX2 shRNA： A)以线性、剂量依赖的方式减弱房颤的电/结构重构，以及b)具有良好的 安全配置文件。在第一阶段，具体目标1，RTI将确定用于运输的最佳电穿孔参数。 使用Firmap导管进行静脉心房基因输送。在第二阶段，具体目标1，我们将确定 NOX2 shRNA预防房颤心力衰竭模型心房纤维化的最佳治疗剂量。同相 二、特定目标2，我们将确定：a)NOX2 shRNA逆转的最佳治疗剂量 房颤快速心房起搏模型中电重构的建立及NOX2的作用持续时间 ShRNA在相同房颤模型逆转房颤中的作用。在第二阶段，具体目标3，RTI将进行关键的毒理学 及其组合产物的生物分布研究。AF是一个价值超过20亿美元的市场。RTI的治疗作用 这种方法如果成功，预计将在目前药物和药物治疗成功的基础上显著改善 房颤的消融策略，从而导致房颤治疗模式的转变。

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.