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

房颤(房颤)是美国等发达国家最常见的心律失常。房颤 严重影响患者的生活，导致从心悸到疲劳、虚弱、 运动不耐受、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45万人入院，房颤造成的医疗成本高达260亿美元。 房颤造成的问题是缺乏安全有效的治疗这种节律紊乱的方法。 房颤的药物治疗有很长的历史，疗效不佳，而且有潜在的致命性副作用。烧蚀 治疗阵发性房颤有一定疗效，但消融术会杀死心脏组织，并不能治愈房颤。我们 有大量的临床前数据表明AdKCNH2-G628S基因绘制安全有效 预防房颤。我们建议进行AdKCNH2-G628S基因涂抹的I期临床试验，以防止后 手术房颤(POAF)。治疗将在心脏手术时进行。我们选择POAF作为 最初的临床目标是因为这是一个至关重要的临床问题，但POAF的风险是暂时的。去治疗 对于所有形式的房颤，我们需要永久性地改变心房，因为房颤的风险永远不会消失。 永久基因表达是首个人类研究的一个关键的安全问题。POAF风险存在于%2 心脏手术后几周，这与腺病毒载体有限的基因表达持续时间相匹配。我们的 POAF基因治疗临床试验将解决一个临床重要问题，同时积累安全性和 以后将应用于永久表达基因转移治疗所有房颤的疗效数据 向量。为了在这项提议中取得成功，我们从R61目标开始：建立一个 最大限度地成功完成房颤基因治疗的早期临床试验。之后 完成R61的工作后，我们将继续R33的目标：成功完成 AdKCNH2-G628S基因治疗POAF的研究为了安全而有效地实现R33目标，我们将其细分 进入使用常规3+3研究设计的初始剂量范围研究，以及随后的随机 两种病毒剂量对心脏手术患者控制效果的比较。这项研究设计将使我们能够 区分心脏手术后典型的生理变化和并发症以及对心脏手术的影响 我们的基因疗法。拆分研究设计将为我们提供足够的数据来推动产品的发展 在发展的同时，仍然尊重这项首个人类研究的安全预防措施。成功完成 我们的目标将是迈向我们最终目标的第一步，即通过绘制心房基因来消除所有房颤。

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.