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Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy

Gene Therapy volume 30, pages 543–551 (2023)Cite this article

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Abstract

Ischemic cardiomyopathy is a leading cause of death and an unmet clinical need. Adeno-associated virus (AAV) gene-based therapies hold great promise for treating and preventing heart failure. Previously we showed that muscle A-kinase Anchoring Protein β (mAKAPβ, AKAP6β), a scaffold protein that organizes perinuclear signalosomes in the cardiomyocyte, is a critical regulator of pathological cardiac hypertrophy. Here, we show that inhibition of mAKAPβ expression in stressed adult cardiomyocytes in vitro was cardioprotective, while conditional cardiomyocyte-specific mAKAP gene deletion in mice prevented pathological cardiac remodeling due to myocardial infarction. We developed a new self-complementary serotype 9 AAV gene therapy vector expressing a short hairpin RNA for mAKAPβ under the control of a cardiomyocyte-specific promoter (AAV9sc.shmAKAP). This vector efficiently downregulated mAKAPβ expression in the mouse heart in vivo. Expression of the shRNA also inhibited mAKAPβ expression in human induced cardiomyocytes in vitro. Following myocardial infarction, systemic administration of AAV9sc.shmAKAP prevented the development of pathological cardiac remodeling and heart failure, providing long-term restoration of left ventricular ejection fraction. Our findings provide proof-of-concept for mAKAPβ as a therapeutic target for ischemic cardiomyopathy and support the development of a translational pipeline for AAV9sc.shmAKAP for the treatment of heart failure.

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Fig. 1: Targeting of mAKAPβ protects against isoproterenol-induced cardiomyocyte death in vitro.
Fig. 2: Cardiomyocyte-specific mAKAPβ knock-out prevents systolic dysfunction following myocardial infarction.
Fig. 3: A new shRNA gene therapy vector inhibits mAKAPβ expression.
Fig. 4: AAV9sc.shmAKAP treatment attenuates systolic dysfunction and prevents heart failure following myocardial infarction in mice.

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Data availability

Additional data and original echocardiographic images are available from the corresponding author on reasonable request.

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Funding

This work was supported by NIH Grants R01HL126825, R01HL153835, and R01HL146111 (Dr. Kapiloff and Dr. Dodge-Kafka) and the NHLBI Gene Therapy Resource Program.

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Authors and Affiliations

  1. Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33101, USA

    Eliana C. Martinez, Jinliang Li, Hrishikesh Thakur & Michael S. Kapiloff

  2. Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA, 94304, USA

    Jinliang Li, Hrishikesh Thakur & Michael S. Kapiloff

  3. Department of Cardiothoracic Surgery and Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305, USA

    Jennifer Arthur Ataam & Ioannis Karakikes

  4. Calhoun Center for Cardiology, University of Connecticut Health Center, Farmington, CT, 06030, USA

    Kristin Tokarski & Kimberly Dodge-Kafka

Authors
  1. Eliana C. Martinez
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  8. Michael S. Kapiloff
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Contributions

ECM performed in vivo mouse research and analysis of primary data with the assistance of JL and HT. JAA performed human induced cardiomyocyte experiments. KT performed rat cardiomyocyte experiments. MSK, ECM, IK, and KDK wrote the paper. MSK provided overall supervision for the project.

Corresponding author

Correspondence to Michael S. Kapiloff.

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Ethical approval

Animal research was approved by the Institutional Animal Care and Use Committee at the University of Miami and the University of Connecticut. The Stanford University Institutional Review Board approved the use of pluripotent stem cells.

Competing interests

Drs. Kapiloff and Li are inventors of patent-protected intellectual property concerning the targeting of mAKAPβ signalosomes to treat heart failure, by which they, the University of Miami, and Stanford University may gain royalties from future commercialization. Dr. Kapiloff holds equity in Anchored RSK3 Inhibitors, LLC, and Cardiac RSK3 Inhibitors, LLC, companies interested in developing mAKAP signalosome-targeted therapies.

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Martinez, E.C., Li, J., Ataam, J.A. et al. Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy. Gene Ther 30, 543–551 (2023). https://doi.org/10.1038/s41434-022-00321-w

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  • DOI: https://doi.org/10.1038/s41434-022-00321-w

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