Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice.
Nat Commun
; 5: 5515, 2014 Dec 02.
Article
em En
| MEDLINE
| ID: mdl-25463264
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
RNA Mensageiro
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Terapia Genética
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Proteínas de Transporte
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Cardiomiopatia Hipertrófica Familiar
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article