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<p>Mutations in <i>LMNA</i>, 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 <i>Lmna</i><sup>−/−</sup> mice. An adeno-associated virus vector expressing wild-type <i>Lmna</i> (AAV-<i>Lmna</i>/DJ8) was administered intrathoracically to neonatal mice. Three weeks after injection, treated <i>Lmna</i><sup>−/−</sup> mice exhibited robust cardiac <i>Lmna</i> mRNA induction and correct nuclear localization of lamin A protein, indicating efficient cardiotropic gene delivery. Compared with PBS treatment, AAV-<i>Lmna</i>/DJ8 treatment promoted body weight maintenance, improved left ventricular systolic function, and significantly prolonged survival in <i>Lmna</i><sup>−/−</sup> mice. To explore the underlying mechanisms, we performed single-nucleus RNA sequencing of cardiomyocytes from wild-type mice, PBS-treated <i>Lmna</i><sup>−/−</sup> mice, and AAV-<i>Lmna</i>/DJ8–treated <i>Lmna</i><sup>−/−</sup> 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 <i>Lmna</i><sup>−/−</sup> mice. These findings demonstrate that targeted re-expression of <i>Lmna</i> partially ameliorates cardiac dysfunction in <i>Lmna</i><sup>−/−</sup> mice and highlight the therapeutic potential of <i>LMNA</i> gene replacement for laminopathy-associated cardiomyopathy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Miho Izawa,
  • Kenji Onoue,
  • Yu Fujiwara,
  • Takahiro Jimba,
  • Tomoko Ioka,
  • Mikako Katagiri,
  • Yasuki Nakada,
  • Hitoshi Nakagawa,
  • Seitaro Nomura,
  • Shungo Hikoso

摘要

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.