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

AdKCNH2-G628S 基因治疗术后房颤的 I 期试验

• 批准号: 10276899
• 负责人: J Kevin Donahue
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10276899
• 关键词: Abbreviations; Ablation; Action Potentials; Address; Adenovirus Vector; Adenoviruses; Affect; American; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Attention; Cardiac Surgery procedures; Cessation of life; Clinical; Congestive Heart Failure; Coupled; Data; Dependovirus; Developed Countries; Development; Disease; Dose; Electrophysiology (science); Elements; Family suidae; Fatigue; Gene Expression; Gene Mutation; Gene Transfer; Genes; Goals; Good Clinical Practice; Health Care Costs; Heart; Heart Atrium; Heart failure; Hospitalization; Infrastructure; Institutional Practice; Institutional Review Boards; Intervention; Investigational Drugs; Measurable; Modeling; Modification; Muscle Cells; Myocardial; Myocardial Infarction; No-Observed-Adverse-Effect Level; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Palpitations; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Physiological; Postoperative Period; Probability; Procedures; Public Health; Randomized; Recording of previous events; Research Design; Risk; Risk Factors; Safety; Sinus; Stroke; Symptoms; Techniques; Testing; Time; Tissues; Toxic effect; Ventricular Arrhythmia; Virion; Virus; Work; clinical development; early phase clinical trial; effective therapy; first-in-human; gene therapy; gene therapy clinical trial; gene transfer vector; good laboratory practice; heart rhythm; human study; institutional biosafety committee; interest; novel; novel therapeutics; phase I trial; pre-clinical; preclinical efficacy; preclinical safety; prevent; side effect; stroke risk; therapy development; therapy duration

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.

心房颤动 (AF) 是美国和其他发达国家最常见的心律紊乱。 AF 严重影响患者的生活，引起心悸、疲劳、虚弱等症状， 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， 每年因 AF 导致的住院人数超过 450,000 例，医疗费用高达 260 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。消融 策略对阵发性房颤有一定疗效，但消融会杀死心脏组织，并且不能治愈房颤。我们 拥有大量临床前数据表明AdKCNH2-G628S基因绘制安全有效 防止房颤。我们建议进行 AdKCNH2-G628S 基因涂色的 I 期临床试验，以预防术后 手术性房颤 (POAF)。治疗将在心脏手术时进行。我们选择 POAF 作为 初始临床目标，因为这是一个极其重要的临床问题，但 POAF 风险是暂时的。治疗 对于所有形式的房颤，我们都需要永久性地改变心房，因为房颤风险永远不会消失。 永久基因表达是首次人体研究的一个关键安全问题。 2 人存在 POAF 风险 心脏手术后几周，这符合腺病毒载体基因表达的有限持续时间。我们的 POAF基因治疗临床试验将解决临床上的重要问题，同时积累安全性和有效性 疗效数据稍后将应用于通过永久表达基因转移治疗所有 AF 向量。为了成功实现这一提案，我们从 R61 目标开始：建立一个基础设施 最大限度地提高成功完成 AF 基因治疗早期临床试验的可能性。后 完成R61工作后，我们转向R33目标：成功完成I期临床试验 AdKCNH2-G628S 基因治疗 POAF。为了安全而有效地实现 R33 目标，我们将其细分 使用传统的 3+3 研究设计和随后的随机研究进行初始剂量范围研究 比较 2 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及其影响 我们的基因疗法。分割研究设计将为我们提供足够的数据来推动产品的发展 开发的同时仍然尊重这项首次人体研究的安全预防措施。顺利完成 我们的目标将是实现通过心房基因绘制消除所有房颤的最终目标的第一步。