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  • Review Article
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Gene therapy for cardiac arrhythmias

Nature Reviews Cardiology (2025)Cite this article

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Abstract

Cardiovascular diseases are the leading cause of death globally, with cardiac arrhythmias contributing substantially to this burden. Gene therapy, which directly targets the underlying disease pathobiology, offers an appealing treatment strategy for cardiac arrhythmias owing to its potential as a one-time, curative solution. Over the past two decades, substantial efforts have been made to develop new gene therapy approaches that overcome the limitations of conventional treatments. In this Review, we describe the rationale for gene therapy to treat cardiac arrhythmias; discuss advantages and disadvantages of gene silencing, gene replacement, gene suppression-and-replacement and gene editing technologies; summarize vector modalities and delivery approaches used in the field; present examples of gene therapy strategies used for atrial and ventricular arrhythmias; and highlight the current challenges and limitations in the gene therapy field.

Key points

  • Available treatments for cardiac arrhythmias mainly focus on symptom management, fail to address the underlying disease substrate and are associated with substantial adverse effects, which makes gene therapy a promising alternative.

  • Key gene therapy strategies in cardiology involve gene silencing, gene replacement, direct genome editing and hybrid gene suppression and replacement to address various cardiac conditions at the genetic level.

  • Vector delivery poses substantial challenges in achieving targeted gene transfer to the heart while minimizing off-target effects; however, promising strategies include receptor-mediated targeting and tissue-specific promoters to improve cardiac specificity.

  • Suppression-and-replacement gene therapy is a variant-independent approach that can be effective for any monogenic dominant-negative disease, and proof-of-principle therapeutic efficacy has been demonstrated in a transgenic rabbit model of type 1 long QT syndrome.

  • Challenges such as immune responses, delivery efficiency and the limited size capacity of viral vectors remain important barriers to the successful clinical translation of gene therapy.

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Fig. 1: Gene therapy strategies.
Fig. 2: Mechanisms underlying selected inherited cardiac arrhythmias.
Fig. 3: SupRep gene therapy for type 1 LQTS.

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Acknowledgements

S.B. thanks the Mayo Clinic Medical Scientist Training Program for fostering an outstanding environment for physician–scientist training. M.J.A. is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, Rochester, MN, USA.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA

    Sahej Bains, John R. Giudicessi & Michael J. Ackerman

  2. Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN, USA

    John R. Giudicessi & Michael J. Ackerman

  3. Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bern, Switzerland

    Katja E. Odening

  4. Department of Paediatric and Adolescent Medicine, Division of Paediatric Cardiology, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

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S.B. researched data for the article and wrote the manuscript. All the authors discussed its content and reviewed/edited the manuscript before submission.

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Correspondence to Michael J. Ackerman.

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S.B. and the Mayo Clinic have a license agreement with Solid Biosciences. M.J.A. is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daichii Sankyo, Illumina, Invitae, Medtronic, Tenaya Therapeutics and UpToDate. M.J.A. and the Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Prolaio, Solid Biosciences and Thryv Therapeutics. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks Lia Crotti, who coreviewed with Luca Sala, and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Bains, S., Giudicessi, J.R., Odening, K.E. et al. Gene therapy for cardiac arrhythmias. Nat Rev Cardiol (2025). https://doi.org/10.1038/s41569-025-01168-5

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