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

基本信息

批准号：
9476321
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
项目类别：
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/9476321
关键词：
Ablation Address Admission activity Adverse effects Adverse event Affect Animals Anti-Arrhythmia Agents Arrhythmia Atrial Fibrillation Ca(2+)-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 Symptoms Testing Toxic effect adeno-associated viral vector adenoviral-mediated base calmodulin-dependent protein kinase II effective therapy gene therapy heart rhythm inhibitor/antagonist novel pre-clinical preclinical development prevent programs public health relevance research clinical testing response stroke risk structural heart disease success transgene expression vector biodistribution

项目摘要

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，严重影响患者的生活，引起心悸、疲劳、虚弱和活动不耐受等症状。大幅增加中风、充血性心力衰竭和死亡的风险，对公共健康造成巨大影响，每年导致超过 45 万人住院，医疗费用增加 260 亿美元。房颤引起的问题之一是缺乏针对这种节律紊乱的安全有效的治疗方法，房颤的药物治疗长期以来一直疗效不佳，并且可能产生致命的副作用，但消融策略在治疗阵发性房颤方面取得了进展，但其过程漫长且困难。我们提出基因疗法作为治疗 AF 的新策略，我们认为永久改变心房传导和难治性特性将安全有效地消除 AF。和房颤猪模型的安全数据表明，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，我们在心房基因涂敷后没有发现致心律失常或其他负面影响。 AAV 介导的 AF 基因治疗具有以下具体目标：(1) 确定长期消除结构性心脏病受试者 AF 的最佳基因转移策略，(2) 评估剂量反应通过基因转移消除 AF 的功效，(3) 评估拟议 AAV 疗法的移动载体生物分布和心房涂敷的安全性，成功完成这些目标将在这种潜在的挽救生命的疗法进入临床试验之前完成所有必要的临床前测试。