Final preclinical development of AAV gene therapy for atrial fibrillation

 描述(申请人提供)：房颤(房颤)是美国和其他发达国家最常见的心律失常。房颤严重影响患者的生活，导致从心悸到疲劳、虚弱和活动不耐受等一系列症状，并大幅增加中风、充血性心力衰竭和死亡的风险。这对公共健康的影响是巨大的，每年有超过45万人入院，医疗费用高达260亿美元。房颤造成的问题是缺乏安全有效的治疗这种节律紊乱的方法。房颤的药物治疗有很长的历史，疗效不佳，而且有潜在的致命性副作用。阵发性房颤的消融策略正在取得进展，但消融过程漫长而困难，成功率不高，不良事件太频繁。我们建议将基因治疗作为治疗房颤的新策略。在这项建议中，我们假设永久改变心房传导和不应性特性将安全有效地消除房颤。我们在猪房颤模型中的有效性和安全性数据表明，预防或逆转电和结构重构的干预措施可以消除心房纤颤的能力。绘制心房基因后，未见心律失常或其他不良反应。在这里，我们建议对AAV介导的基因治疗房颤进行正式的临床前测试，具体目的如下：(1)确定长期消除结构性心脏病患者房颤的最佳基因转移策略，(2)评估基因转移消除房颤的疗效的剂量-反应关系，(3)评估所建议的AAV治疗的载体生物分布和心房涂抹的安全性。成功完成这些目标将完成所有必要的临床前测试，然后将这一潜在的挽救生命的疗法转移到临床试验中。

 DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of stroke, congestive heart failure and death. The impact on public health is substantial, with more than 450,000 hospital admissions per year and $26 billion in healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. We propose gene therapy as a new strategy to treat AF. In this proposal, we hypothesize that permanent modification of atrial conduction and refractory properties will safely and effectively eliminate AF. We have efficacy and safety data in a pig model of AF showing that interventions to prevent or reverse electrical and structural remodeling can eliminate the ability of the atria to fibrillate. We saw no proarrhythmia or other negative effects after atrial gene painting. Here, we propose formal preclinical testing of AAV-mediated gene therapy for AF with the following specific aims: (1) To define the best gene transfer strategy for long-term elimination of AF in subjects with structural heart disease, (2) To evaluate dose-response for efficacy of AF elimination by gene transfer, (3) To evaluate vector biodistribution and safety for atrial painting of the proposed AAV therapy. Successful completion of these aims will complete all necessary preclinical testing before moving this potential life-saving therapy to clinical tria.