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Updated: Apr 20, 2026
Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice
Giulia Mearini1, Doreen Stimpel1, Birgit Geertz1
11] 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.
Insights
Gene therapy successfully treated neonatal hypertrophic cardiomyopathy (HCM) in mice by restoring cardiac myosin-binding protein C (cMyBP-C) levels and preventing disease progression. This approach offers a potential new treatment for severe infant heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Gene Therapy
Background:
- Neonatal hypertrophic cardiomyopathy (HCM) is caused by MYBPC3 mutations, leading to rapid heart failure and death.
- Current treatments are limited, with heart transplantation being the only alternative.
Purpose of the Study:
- To evaluate the long-term efficacy of Mybpc3 gene therapy in a mouse model of neonatal HCM.
- To assess the impact of gene therapy on cardiac function, gene expression, and mutant mRNA levels.
Main Methods:
- Systemic administration of adeno-associated virus (AAV9)-Mybpc3 to neonatal Mybpc3-targeted knock-in (KI) mice.
- Monitoring cardiac hypertrophy, dysfunction, and Mybpc3 expression over 34 weeks.
- Quantification of Mybpc3 mRNA and cardiac myosin-binding protein C (cMyBP-C) protein levels.
Main Results:
- A single gene therapy dose prevented cardiac hypertrophy and dysfunction in KI mice for 34 weeks.
- Mybpc3 gene therapy increased Mybpc3 mRNA and cMyBP-C protein levels dose-dependently.
- Gene therapy also suppressed the accumulation of mutant MYBPC3 mRNAs.
Conclusions:
- This study demonstrates the first successful long-term gene therapy for neonatal HCM.
- Mybpc3 gene therapy corrects both haploinsufficiency and the production of toxic peptides.
- Gene therapy presents a potential therapeutic option for severe neonatal HCM, offering hope beyond heart transplantation.
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.
