A phase I trial of AdKCNH2-G628S gene therapy for post-op atrial fibrillation

心房颤动（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，导致从心悸到疲劳，虚弱， 活动不耐受、中风、充血性心力衰竭和死亡。对公众健康的影响是巨大的， 每年有超过450，000例住院病例和260亿美元的医疗费用可归因于AF。 除了房颤引起的问题之外，还缺乏一种安全有效的治疗这种心律失常的方法。 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 这些治疗策略对阵发性房颤有一定的疗效，但消融会杀死心脏组织，不能治愈房颤。 有大量的临床前数据显示AdKCNH 2-G628 S基因涂染安全有效， 我们建议进行一项AdKCNH 2-G628 S基因涂染的I期临床试验，以预防AF后， 手术性房颤（POAF）。治疗将在心脏手术时应用。我们选择POAF作为 初始临床目标，因为它是一个非常重要的临床问题，但POAF风险是暂时的。治疗 所有形式的房颤，我们都需要永久性地修改心房，因为房颤风险永远不会消失。 永久性基因表达是首次人体研究的关键安全性问题。POAF风险存在2 这与腺病毒载体基因表达的有限持续时间相吻合。我们 POAF基因治疗临床试验将解决临床上重要的问题，同时积累安全性和 随后将应用于永久表达基因转移治疗所有AF的疗效数据 向量。为了成功地实现这一建议，我们从R61目标开始：建立一个基础设施， 最大化成功完成AF基因治疗早期临床试验的可能性。后 完成R61的工作后，我们将转向R33的目标：成功完成一项I期临床试验， AdKCNH 2-G628 S基因治疗原发性房颤为了安全而有效地解决R33目标，我们将其细分为 使用传统的3+3研究设计进行初始剂量范围研究， 比较两种病毒剂量以控制心脏手术患者。这项研究设计将使我们能够 区分典型的心脏手术后生理变化和并发症以及 我们的基因疗法分开的研究设计将为我们提供足够的数据来推动产品的发展 开发，同时仍然尊重这项首次人体研究的安全预防措施。成功完成 我们的目标将是实现我们最终目标的第一步，即通过心房基因涂绘消除所有房颤。

Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects patients' lives, causing symptoms that range from palpitations to fatigue, weakness, activity intolerance, 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 attributable to AF. Adding to the problems caused by AF is the lack of a safe and effective therapy for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Ablation strategies have some efficacy for paroxysmal AF, but ablation kills heart tissue and it does not cure AF. We have extensive preclinical data showing that AdKCNH2-G628S gene painting safely and effectively prevents AF. We propose a phase I clinical trial of AdKCNH2-G628S gene painting to prevent post- operative AF (POAF). Therapy would be applied at the time of cardiac surgery. We choose POAF as the initial clinical target because it is a critically important clinical problem but POAF risk is temporary. To treat all forms of AF, we would need to permanently modify the atria because AF risk never goes away. Permanent gene expression is a critical safety concern for first-in-human study. POAF risk is present for 2 weeks after cardiac surgery, which fits the limited duration of gene expression with adenovirus vectors. Our POAF gene therapy clinical trial will address a clinically important problem while accumulating safety and efficacy data that will later be applied to treatment of all AF with permanently expressing gene transfer vectors. To succeed in this proposal, we start with an R61 aim: To establish an infrastructure that maximizes probability of successfully completing the early phase clinical trial for AF gene therapy. After finishing the R61 work, we move on to an R33 aim: To successfully complete a Phase I clinical trial of AdKCNH2-G628S gene therapy for POAF. To safely but effectively address the R33 aim, we subdivide it into an initial dose-ranging study using a conventional 3+3 study design and a subsequent randomized comparison of 2 virus doses to control cardiac surgery patients. This study design will allow us to distinguish between typical post-cardiac surgery physiological changes and complications and the effects of our gene therapy. The split study design will give us sufficient data to move the product forward in development while still respecting safety precautions for this first-in-human study. Successful completion of our aims will be the first step toward our eventual goal of eliminating all AF with atrial gene painting.