Final preclinical development of AAV gene therapy for atrial fibrillation

 描述（由申请人提供）：房颤（AF）是美国和其他发达国家最常见的心律失常。AF严重影响患者的生活，引起从心悸到疲劳、虚弱和活动不耐受的症状，并大大增加中风、充血性心力衰竭和死亡的风险。对公共卫生的影响是巨大的，每年有超过450，000人住院，医疗费用为260亿美元。除了房颤引起的问题外，还缺乏针对这种节律紊乱的安全有效的治疗方法。房颤的药物治疗具有疗效差和潜在致命副作用的悠久历史。消融策略正在阵发性房颤中取得进展，但它们是长期的、困难的手术，成功率低于最佳水平，不良事件太频繁。我们提出基因治疗作为一种新的策略来治疗AF。在这个建议中，我们假设，永久修改心房传导和不应特性将安全有效地消除AF。我们有疗效和安全性数据在猪AF模型显示，干预措施，以防止或逆转电和结构重塑可以消除心房的能力，以avoidate。心房基因涂绘后，我们没有看到致心律失常或其他负面影响。在这里，我们提出了正式的临床前试验的AAV介导的基因治疗AF与以下具体目标：（1）以确定最佳的基因转移策略，长期消除AF的受试者与结构性心脏病，（2）以评估剂量反应的AF消除疗效的基因转移，（3）以评估载体的生物分布和安全性心房画的AAV治疗。成功完成这些目标将完成所有必要的临床前测试，然后将这种潜在的挽救生命的疗法推向临床试验。

 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.