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Updated: Nov 3, 2025
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure
Anca Remes1,2,3, Andreas H Wagner2, Nesrin Schmiedel1,3
1Department of Internal Medicine III, University Hospital Schleswig-Holstein and University of Kiel , Arnold-Heller-Str. 3 , Kiel, Germany.
Abstract:
Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.
Insights
Neutralizing specific transcription factors with RNA decoys prevents heart failure. This novel AAV-mediated gene therapy approach targets nuclear factor of activated T cells (NFAT) to combat cardiac hypertrophy.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Therapy
Background:
- Nuclear factor of activated T cells (NFAT) plays a critical role in hypertension-induced myocardial hypertrophy, a precursor to heart failure.
- Existing therapeutic strategies for heart failure often have limitations, necessitating novel approaches.
Purpose of the Study:
- To investigate the therapeutic potential of neutralizing NFAT transcription factors (NFATc1-c4) using RNA-based decoy oligonucleotides (dONs) delivered via adeno-associated virus (AAV) for treating myocardial hypertrophy and heart failure.
Main Methods:
- Developed AAV vectors for cardiac-specific expression of dONs targeting NFATc1-c4.
- Assessed the efficacy of dONs in reducing endothelin-1 induced cardiomyocyte hypertrophy in vitro.
- Evaluated dON expression in the hearts of adult mice using fluorescent in situ hybridization.
- Administered AAV-mediated dONs to mice before and after transverse aortic constriction (TAC) to model cardiac hypertrophy and heart failure.
Main Results:
- AAV-mediated dON expression significantly reduced cardiomyocyte hypertrophy in vitro.
- Efficient cardiac expression of dONs was confirmed in vivo.
- Cardiomyocyte-specific dON expression conferred protection against cardiac hypertrophy, remodeling, and heart failure development in mice subjected to TAC.
- Therapeutic effects were observed regardless of whether dONs were administered before or after TAC induction.
Conclusions:
- AAV-mediated delivery of RNA-based decoy oligonucleotides targeting NFAT transcription factors is a potent strategy to prevent and treat cardiac hypertrophy and heart failure.
- This approach offers a novel therapeutic avenue for cardiovascular diseases driven by NFAT signaling.
- Systemic administration of AAVs for cell-specific gene neutralization represents a promising therapeutic modality.
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