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Nat Commun. 2014 Dec 2;5:5515. doi: 10.1038/ncomms6515.

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

Author information

1
1] Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
2
1] Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Hamburg, Germany [3] Hamburg Zentrum für Experimentelle Therapie Forschung (HEXT) Vector Core Unit, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
3
1] Department of Cardiology, Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany [2] DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
4
Université Pierre et Marie Curie UPMC-Inserm UMR S974, CNRS FRE 3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris F-75013, France.

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.

PMID:
25463264
DOI:
10.1038/ncomms6515
[Indexed for MEDLINE]

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