Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Giulia Mearini, Doreen Stimpel, Birgit Geertz, Florian Weinberger, Elisabeth Krämer, Saskia Schlossarek, Julia Mourot-Filiatre, Andrea Stoehr, Alexander Dutsch, Paul J M Wijnker, Ingke Braren, Hugo A Katus, Oliver J Müller, Thomas Voit, Thomas Eschenhagen, Lucie Carrier

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

Original languageEnglish
Article number5515
JournalNature Communications
Publication statusPublished - 2 Dec 2014

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