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

基本信息

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
项目类别：
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

项目摘要

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节奏扰动。 AF 显着影响患者的生活，引起症状，从心per到疲劳，无力，活动不耐受，中风，充血性心力衰竭和死亡。对公共卫生的影响很大，每年有超过450,000次住院和260亿美元的医疗保健费用归因于AF。除了AF引起的问题外，还缺乏对这种节奏障碍的安全有效疗法。 AF的药物疗法的功效不良和潜在致命的副作用的史。消融策略对阵发性AF具有一定的功效，但是消融会杀死心脏组织，并且无法治愈AF。我们拥有广泛的临床前数据，表明ADKCNH2-G628S基因绘画安全有效地绘画防止AF。我们提出了ADKCNH2-G628S基因绘画的I期临床试验，以防止后手术AF（POAF）。在心脏手术时将应用治疗。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风险是暂时的。治疗所有形式的AF，我们都需要永久修改心房，因为AF风险永远不会消失。永久基因表达是人类第一研究的关键安全问题。有2个POAF风险心脏手术后几周，与腺病毒载体的基因表达持续时间有限。我们的 POAF基因疗法临床试验将在累积安全性和疗效数据后来将应用于用永久表达基因转移的所有AF的治疗向量。为了在该建议中取得成功，我们从R61的目标开始：建立一个基础设施最大化成功完成AF基因治疗的早期临床试验的可能性。后完成R61的工作，我们继续进行R33目标：成功完成I期临床试验 POAF的ADKCNH2-G628S基因疗法。为了安全但有效地解决R33目标，我们将其细分使用常规的3+3研究设计和随后的随机分组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后心外科手术生理变化和并发症以及我们的基因疗法。分裂研究设计将为我们提供足够的数据，以将产品推向前进开发同时仍尊重这项人类研究的安全预防措施。成功完成我们的目标将是朝着我们最终的目标迈出的目标迈出的第一步，即用房屋绘画消除所有AF。