title: Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice.
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.
authors.affiliation: 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.
authors.forename: Giulia
authors.initials: G
authors.lastname: Mearini
authors.affiliation: 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.
authors.forename: Doreen
authors.initials: D
authors.lastname: Stimpel
authors.affiliation: 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.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geertz
authors.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Weinberger
authors.affiliation: 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.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Krämer
authors.affiliation: 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.
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.affiliation: 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.
authors.forename: Julia
authors.initials: J
authors.lastname: Mourot-Filiatre
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stoehr
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dutsch
authors.affiliation: 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.
authors.forename: Paul J M
authors.initials: PJ
authors.lastname: Wijnker
authors.affiliation: 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.
authors.forename: Ingke
authors.initials: I
authors.lastname: Braren
authors.affiliation: 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.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: 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.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: Université Pierre et Marie Curie UPMC-Inserm UMR S974, CNRS FRE 3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris F-75013, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: 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.
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
mesh_terms: D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus; D055879:Gene Knock-In Techniques; D015316:Genetic Therapy / Q000379:methods*; D006720:Homozygote; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism*; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C