Final preclinical development of AAV gene therapy for atrial fibrillation

房颤 AAV 基因治疗的最终临床前开发

• 批准号: 9288221
• 负责人: J Kevin Donahue
• 金额: $ 72.14万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288221
• 关键词: Ablation; Address; Admission activity; Adverse effects; Adverse event; Affect; Animals; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Calcium/calmodulin-dependent protein kinase; Cessation of life; Clinical; Congestive Heart Failure; Connexin 43; Connexins; Data; Dependovirus; Developed Countries; Developing Countries; Disease; Dose; Family suidae; Fatigue; Gene Transfer; Genes; Goals; Health Care Costs; Heart Atrium; Hospitals; Human; Intervention; Life; Lung diseases; Mediating; Medical; Modeling; Modification; Muscle Cells; Mutation; Palpitations; Patient Care; Patients; Pharmacotherapy; Potassium Channel; Preclinical Testing; Procedures; Property; Public Health; Recording of previous events; Refractory; Risk; Safety; Savings; Stroke; Symptoms; Testing; Toxic effect; adeno-associated viral vector; adenoviral-mediated; base; effective therapy; gene therapy; heart rhythm; inhibitor/antagonist; novel; pre-clinical; preclinical development; prevent; programs; public health relevance; research clinical testing; response; structural heart disease; success; transgene expression; vector biodistribution

 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.

 描述（由申请人提供）：心房颤动（AF）是美国和其他发达国家最常见的节律紊乱。房颤显着影响患者的生活，引起心悸、疲劳、虚弱和活动不耐受等症状，并大大增加中风、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 万人入院治疗，医疗费用高达 260 亿美元。房颤造成的问题更为严重的是，缺乏针对这种节律紊乱的安全有效的治疗方法。房颤药物治疗长期以来一直疗效不佳，并有潜在致命的副作用。消融策略在阵发性房颤治疗中取得了进展，但它们是漫长而困难的手术，成功率较低，而且不良事件过于频繁。我们建议基因治疗作为治疗 AF 的新策略。在该提案中，我们假设永久改变心房传导和耐火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塑的干预措施可以消除心房颤动的能力。心房基因绘制后，我们没有看到致心律失常或其他负面影响。在这里，我们建议对 AAV 介导的 AF 基因治疗进行正式的临床前测试，其具体目标如下：(1) 确定结构性心脏病受试者长期消除 AF 的最佳基因转移策略，(2) 评估基因转移消除 AF 功效的剂量反应，(3) 评估所提出的 AAV 治疗心房涂敷的载体生物分布和安全性。成功完成这些目标将完成所有必要的临床前测试，然后再将这种潜在的挽救生命的疗法转移到临床试验。