Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of 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. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. We propose gene therapy as a new strategy to treat AF. In this proposal, we hypothesize that permanent modification of atrial conduction and refractory properties will safely and effectively eliminate AF. We have efficacy and safety data in a pig model of AF showing that interventions to prevent or reverse electrical and structural remodeling can eliminate the ability of the atria to fibrillate. We saw no proarrhythmia or other negative effects after atrial gene painting. Here, we propose formal preclinical testing of AAV-mediated gene therapy for AF with the following specific aims: (1) To define the best gene transfer strategy for long-term elimination of AF in subjects with structural heart disease, (2) To evaluate dose-response for efficacy of AF elimination by gene transfer, (3) To evaluate vector biodistribution and safety for atrial painting of the proposed AAV therapy. Successful completion of these aims will complete all necessary preclinical testing before moving this potential life-saving therapy to clinical tria.
Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of 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 added healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Newer ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. This proposal focuses on developing gene therapy to treat and potentially cure AF. We have preliminary data showing that gene therapies can eliminate AF. In this proposal, we will complete all of the necessary preclinical testing for AF gene therapy which will give sufficient data for testing in humans.
| Finet, J Emanuel; Wan, Xiaoping; Donahue, J Kevin (2018) Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer. Virology 513:43-51 |
| Donahue, J Kevin (2018) Sequencing of uncertain significance. J Cardiovasc Electrophysiol 29:105-106 |
| Donahue, J Kevin (2017) Current state of the art for cardiac arrhythmia gene therapy. Pharmacol Ther 176:60-65 |
