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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL130376-01
Application #
9007997
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2016-07-01
Project End
2020-04-30
Budget Start
2016-07-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
$721,436
Indirect Cost
$290,728
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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