Abstract 11841: Gene Therapy Improves Pathological Cardiac Remodeling in Human Hypertrophic Cardiomyopathy Gene Variant Knock-In Mice

Abstract

Introduction: Some patients with hypertrophic cardiomyopathy (HCM) has been reported to develop ventricular systolic dysfunction, called the dilated phase of HCM (d-HCM). Although d-HCM is associated with increased morbidity and mortality, precise mechanism for the development of the pathological cardiac remodeling and gene-targeted therapy are still under investigation. It has been shown that cardiac myosin binding protein C (Mybpc3) missense mutation (R820Q) is associated with familial HCM and d-HCM. Methods and Results: We generated a knock-in mouse model, carrying the R820Q mutation of Mybpc3 (MyBP-KI mice). MyBP KI mice spontaneously developed cardiac hypertrophy and mild systolic dysfunction at 8 weeks of age, reproducing the d-HCM phenotype, while their littermate control mice showed normal cardiac mass and function. Transcriptome analysis by RNA-seq showed that, in addition to upregulation of heart failure-related fetal genes, mitochondria-related gene sets (oxidative phosphorylation and fatty acid metabolism) were suppressed in MyBP-KI mice compared to control mice. We examined adeno-associated virus (AAV)-mediated gene therapy on MyBP-KI mice. AAV vectors with wild type Mybpc3 controlled by the cardiac troponin T promoter were administered intravenously to MyBP-KI mice that began to develop hypertrophy at 8 weeks of age. Echocardiography and cardiac catheter examinations showed that the deterioration of cardiac function over time was significantly suppressed by AAV gene therapy. Overexpression of fetal genes of cardiomyocyte was significantly suppressed, mitochondrial gene abnormalities were also significantly attenuated, and histological myocardial fibrosis was also significantly suppressed by administration of AAV harboring wild type Mybpc3. Conclusions: Our MyBP-KI mice spontaneously recapitulated human d-HCM phenotype. Gene therapy with AAV, even when administered at a stage when cardiac remodeling has already begun to progress, successfully suppressed cardiac dysfunction at the genetic level and prevented the transition to d-HCM.