Biodistribution and Toxicology Assessment of Gene Therapy for Postoperative Atrial Fibrillation
Abstract
Atrial fibrillation is an abnormal heart rhythm where the normal heart beat is overwhelmed by a fast chaotic rhythm that takes control of the top chambers of the heart (the atria). Atrial fibrillation is the leading cause of stroke and a significant risk factor for heart failure, heart attack, and death. More than six million Americans are afflicted with atrial fibrillation, making it a significant threat to public health. Military Veterans are particularly vulnerable to atrial fibrillation because factors predisposing to atrial fibrillation development (hypertension, coronary artery disease, tobacco use, diabetes, heart failure) are prevalent in Veterans. A considerable limitation to control of atrial fibrillation is the absence of safe and effective therapies. Heart rhythm-controlling drugs are at best 50% effective at controlling atrial fibrillation, and these drugs are often associated with severe and potentially deadly side effects. Ablation is an invasive procedure where a catheter is used to kill parts of the heart responsible for the abnormal heart rhythm. Since atrial fibrillation often comes from large areas of the atria, ablation is only effective in limited circumstances. Ablation procedures also have substantial risk of major complications. The impact of atrial fibrillation coupled with the limitations in treatment options point to the need for development of novel therapies to conquer this problem. Post-operative atrial fibrillation is a specific form of atrial fibrillation that occurs shortly after cardiothoracic surgery. A unique element of post-operative atrial fibrillation is the limited duration of risk, which peaks 3 days and dissipates 10 days after surgery. Even with this limited duration of risk, post-operative atrial fibrillation is a critically important clinical problem. It increases risk of stroke, heart failure, myocardial infarction, and death. Other than the limited period of risk, post-operative atrial fibrillation is similar to common atrial fibrillation, affecting patients with the same risk factors, acting by the same arrhythmia mechanism, and responding to the same therapies with similar disappointing efficacy. We propose gene therapy for post-operative atrial fibrillation. Gene therapy is a technique where viruses are used to transfer a gene with therapeutic properties into a tissue that could benefit from that therapy. Why focus initially on post-operative atrial fibrillation? To treat common atrial fibrillation, we would need to permanently modify the atria because the risk of common atrial fibrillation never goes away. For post-operative atrial fibrillation, the risk disappears after 2 weeks. This limited duration of risk for post-operative atrial fibrillation allows us to eliminate it with a temporary intervention. We think it is safer to start with a limited duration therapy before attempting the permanent modification that will be required for common atrial fibrillation. To eliminate post-operative atrial fibrillation, we will use an adenovirus that has been modified to cause expression of a gene that slows the recovery of heart cells from each heartbeat, and then use a novel gene painting technique to deliver this virus to the cardiac atria. This property of delaying recovery from the previous heartbeat slows the atria just enough to prevent atrial fibrillation but does not affect normal atrial function. A unique property of adenovirus gene therapy is that it only works for 2-3 weeks, which is a perfect time course for treatment of post-operative atrial fibrillation. We have extensive data showing safety and efficacy of our proposed therapy in an animal model of atrial fibrillation. In this proposal, we will complete the remaining steps necessary to bring atrial gene painting to clinical trial. Successful completion of our proposal will allow us to present an Investigational New Drug application to the United States Food and Drug Administration and i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610229
Entities
People
- John Donahue
Organizations
- United States Army
- University of Massachusetts Medical School