GENE TRANSFER APPROACHES TO ATRIAL FIBRILATION

心房颤动的基因转移方法

基本信息

批准号：
7637836
负责人：
J Kevin Donahue
金额：
$ 39.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

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 400,000 hospital admissions per year and $6-7 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. Newer 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 have proposed gene therapy as a new strategy to treat cardiac arrhythmias. In this proposal, we hypothesize that gene therapy-induced alterations in atrial conduction and refractory properties will prevent atrial fibrillation. To test this hypothesis, we will address 3 specific aims: (1) to define conditions for AF prevention with refractory period prolongation from KCNH2-G628S gene transfer; (2) to assess the relative contributions of IKur and IKr to atrial repolarization during AF and to AF prevention, and (3) to eliminate AF by prolonging atrial refractory properties in combination with increasing atrial connectivity and conduction. Successful completion of these aims will further our understanding of the mechanism responsible for sustaining AF and possibly allow translation of these findings into novel therapies. PUBLIC HEALTH RELEVANCE: 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 400,000 hospital admissions per year and $6-7 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. Newer 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. This proposal focuses on developing new therapies to treat and potentially cure AF. We have preliminary data showing that gene therapies can eliminate AF. In this proposal, we will further develop our understanding of these therapies and their potential use with AF.

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。它对公共健康的影响是巨大的，每年有超过 400,000 人入院治疗，医疗费用达 6-70 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。较新的消融策略正在治疗阵发性房颤，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。我们提出基因疗法作为治疗心律失常的新策略。在这项提议中，我们假设基因治疗引起的心房传导和难治特性的改变将预防心房颤动。为了检验这一假设，我们将实现 3 个具体目标：(1) 确定通过 KCNH2-G628S 基因转移延长不应期的 AF 预防条件； (2) 评估 IKur 和 IKr 对 AF 期间心房复极和 AF 预防的相对贡献，以及 (3) 通过延长心房难治性并结合增加心房连通性和传导来消除 AF。成功完成这些目标将进一步加深我们对维持房颤的机制的理解，并可能将这些发现转化为新的疗法。公共卫生相关性：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。它对公共健康的影响是巨大的，每年有超过 400,000 人入院，医疗费用达 6-70 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。较新的消融策略正在治疗阵发性房颤，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。该提案的重点是开发治疗和潜在治愈 AF 的新疗法。我们有初步数据表明基因疗法可以消除房颤。在本提案中，我们将进一步加深对这些疗法及其治疗 AF 的潜在用途的理解。