Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy

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 beta (mAKAP beta, AKAP6 beta), a scaffold protein that organizes perinuclear signalosomes in the cardiomyocyte, is a critical regulator of pathological cardiac hypertrophy. Here, we show that inhibition of mAKAP beta 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 mAKAP beta under the control of a cardiomyocyte-specific promoter (AAV9sc.shmAKAP). This vector efficiently downregulated mAKAP beta expression in the mouse heart in vivo. Expression of the shRNA also inhibited mAKAP beta 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 mAKAP beta as a therapeutic target for ischemic cardiomyopathy and support the development of a translational pipeline for AAV9sc.shmAKAP for the treatment of heart failure.

Automated summary

Ischemic cardiomyopathy, a leading cause of death, can be treated by inhibiting mAKAP beta expression using the AAV9sc.shmAKAP gene therapy vector. Inhibition of mAKAP beta expression in stressed cardiomyocytes provides cardioprotection, prevents pathological cardiac remodeling, and restores left ventricular ejection fraction. The findings support mAKAP beta as a therapeutic target and the development of AAV9sc.shmAKAP for heart failure treatment.