Cardiomyocyte lamin A re-expression via AAV-Lmna/DJ8 ameliorates cardiac dysfunction in Lmna−/− mice

Abstract

Abstract Mutations in LMNA , which encodes the nuclear envelope protein lamin A/C, cause laminopathies that frequently present as dilated cardiomyopathy (DCM). We investigated whether re-expression of lamin A in cardiomyocytes can rescue the severe phenotype of Lmna −/− mice. An adeno-associated virus vector expressing wild-type Lmna (AAV- Lmna /DJ8) was administered intrathoracically to neonatal mice. Three weeks after injection, treated Lmna −/− mice exhibited robust cardiac Lmna mRNA induction and correct nuclear localization of lamin A protein, indicating efficient cardiotropic gene delivery. Compared with PBS treatment, AAV- Lmna /DJ8 treatment promoted body weight maintenance, improved left ventricular systolic function, and significantly prolonged survival in Lmna −/− mice. To explore the underlying mechanisms, we performed single-nucleus RNA sequencing of cardiomyocytes from wild-type mice, PBS-treated Lmna −/− mice, and AAV- Lmna /DJ8–treated Lmna −/− mice. AAV-mediated lamin A re-expression shifted the cardiomyocyte transcriptome toward the wild-type profile, and restored oxidative phosphorylation–related gene programs, which were diminished in untreated Lmna −/− mice. These findings demonstrate that targeted re-expression of Lmna partially ameliorates cardiac dysfunction in Lmna −/− mice and highlight the therapeutic potential of LMNA gene replacement for laminopathy-associated cardiomyopathy.