# A phase I trial of AdKCNH2-G628S gene therapy for post-op atrial fibrillation

> **NIH NIH R61** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $418,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10276899
- **Project number:** 1R61HL158541-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** J Kevin Donahue
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2021-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276899

## Citation

> US National Institutes of Health, RePORTER application 10276899, A phase I trial of AdKCNH2-G628S gene therapy for post-op atrial fibrillation (1R61HL158541-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10276899. Licensed CC0.

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