| First Author | Martinez EC | Year | 2023 |
| Journal | Gene Ther | Volume | 30 |
| Issue | 7-8 | Pages | 543-551 |
| PubMed ID | 35102273 | Mgi Jnum | J:348552 |
| Mgi Id | MGI:7640277 | Doi | 10.1038/s41434-022-00321-w |
| Citation | Martinez EC, et al. (2023) Targeting mAKAPbeta expression as a therapeutic approach for ischemic cardiomyopathy. Gene Ther 30(7-8):543-551 |
| abstractText | 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 (mAKAPbeta, AKAP6beta), a scaffold protein that organizes perinuclear signalosomes in the cardiomyocyte, is a critical regulator of pathological cardiac hypertrophy. Here, we show that inhibition of mAKAPbeta 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 mAKAPbeta under the control of a cardiomyocyte-specific promoter (AAV9sc.shmAKAP). This vector efficiently downregulated mAKAPbeta expression in the mouse heart in vivo. Expression of the shRNA also inhibited mAKAPbeta 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 mAKAPbeta as a therapeutic target for ischemic cardiomyopathy and support the development of a translational pipeline for AAV9sc.shmAKAP for the treatment of heart failure. |
