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

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

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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（通过应用程序提供）：房颤（AF）是美国和其他发达国家最常见的节奏障碍。 AF显着影响受影响的生活，导致症状，从舒适到疲劳，虚弱和活动摄入量，并大大增加了中风，充血性心力衰竭和死亡的风险。对公共卫生的影响很大，每年有超过450,000次住院和260亿美元的医疗费用。除了AF引起的问题外，还缺乏这种节奏障碍的安全有效疗法。 AF的药物疗法的效率较差和潜在的致命副作用历史悠久。消融策略正在阵发性AF中侵入，但是它们是漫长而困难的程序，其成功率不足，并且经常发生不良事件。我们建议基因疗法作为治疗AF的新策略。在此提案中，我们假设对心房传导和难治性能的永久修改将安全有效地消除AF。我们在AF的猪模型中具有有效性和安全性数据，表明预防或反向电气和结构重塑的干预措施可以消除心房纤维化的能力。我们没有看到心房基因绘画后没有其他心律失常或其他负面影响。 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 efficiency of AF elimination by gene transfer, (3) To evaluate vector biodistribution and safety for atrial painting of the proposed AAV therapy.这些目标的成功完成将完成所有必要的临床前测试，然后再将这种潜在的救生疗法转移到临床三亚临时。