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 and Lucie Carrier ()
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Giulia Mearini: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Doreen Stimpel: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Birgit Geertz: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Florian Weinberger: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Elisabeth Krämer: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Saskia Schlossarek: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Julia Mourot-Filiatre: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Andrea Stoehr: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Alexander Dutsch: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Paul J. M. Wijnker: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Ingke Braren: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Hugo A. Katus: Internal Medicine III, University Hospital Heidelberg
Oliver J. Müller: Internal Medicine III, University Hospital Heidelberg
Thomas Voit: Université Pierre et Marie Curie UPMC-Inserm UMR S974, CNRS FRE 3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris F-75013, France
Thomas Eschenhagen: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf
Lucie Carrier: Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms6515

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