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: 10523697
• 负责人: Robert Charles Moen
• 金额: $ 163.65万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523697
• 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; Persons; 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; 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.

项目总结