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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：
10703247
负责人：
J Kevin Donahue
金额：
$ 121.29万
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703247
关键词：
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 Developed Countries Development Disease Dose Elements Family suidae Fatigue Gene Expression Gene Mutation Gene Transfer Genes Goals Health Care Costs Heart Heart Atrium Heart failure Hospitalization Infrastructure Intervention Measurable Modeling Modification Muscle Cells Myocardial Myocardial Infarction Operative Surgical Procedures Organ Oryctolagus cuniculus Paint 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 Stroke Symptoms Techniques Testing Time Tissues Toxic effect Ventricular Arrhythmia Virus Work clinical development early phase clinical trial effective therapy first-in-human gene therapy gene therapy clinical trial gene transfer vector heart rhythm human study 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心律失常。房颤