Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy

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.

mAKAPβ signalosome: A potential target for cardiac hypertrophy

“…Recently Martinez et al (2022), studied the potential of targeting mAKAPβ as a therapeutic approach for ischemic cardiomyopathy.…”

“…Results obtained from this in-vitro study were supported by an in-vivo study in which MCM mice and mAKAPβ CKO (mAKAPfl/fl) mice were subjected to coronary artery ligation to develop myocardial infarction (MI). The infarct size was less in mAKAPβ CKO and it also prevented cardiac remodeling (Table 1) (Martinez et al, 2022). Another gene therapy technique to downregulate the expression of mAKAPβ was used by inducing mice with self-complementary serotype 9 adeno-associated virus (AAV9sc) consisting of MIR30A shRNA cassettes for mAKAP (AAV9sc.shmAKAP) and control (AAV9sc.shControl).…”

“…Further, atrial Natriuretic Factor (ANF) expression was less in mAKAPβ siRNA cardiomyocytes as compared to siRNA control cardiomyocytes induced with PE (Pare, Bauman, et al, 2005). Recently Martinez et al (2022), studied the potential of targeting mAKAPβ as a therapeutic approach for ischemic cardiomyopathy. From this study, it was observed that the downregulation of mAKAP did not affect cardiomyocyte survival rather it prevented the cell apoptosis of ISO treated cardiomyocytes.…”

“…Post‐MI it was observed that mice induced with AAV9sc.shmAKAP resulted in 49% less infarct size as compared to control, and also prevented cardiac remodeling. This study provided a new method of downregulating the expression of mAKAPβ that can aid in the treatment of ischemic cardiomyopathy (Martinez et al, 2022).…”

A perinuclear calcium compartment regulates cardiac myocyte hypertrophy

“…In vivo evidence for mAKAPβ regulation of pathological cardiac remodeling has been obtained in mice by inducible mAKAPβ gene deletion and by treatment with a mAKAP small hairpin RNA (shRNA) adeno-associated virus gene therapy vector [ 18 , 19 ]. Cardiac myocyte-specific mAKAPβ targeting in the adult inhibited cardiac hypertrophy induced by chronic catecholamine infusion, pressure overload and myocardial infarction.…”