Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy

Eliana C. Martinez, Jinliang Li, Jennifer Arthur Ataam, Kristin Tokarski, Hrishikesh Thakur, Ioannis Karakikes, Kimberly Dodge-Kafka, Michael S. Kapiloff

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalGene Therapy
DOIs
StateAccepted/In press - 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Fingerprint

Dive into the research topics of 'Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy'. Together they form a unique fingerprint.

Cite this