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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy
Jianming Jiang1, Hiroko Wakimoto, J G Seidman
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Insights
Dominant mutations in myosin heavy chains (MHC) cause hypertrophic cardiomyopathy (HCM). Silencing the mutated cardiac MHC gene in mice prevented HCM development, suggesting a potential therapeutic strategy for patients.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Gene Therapy
Background:
- Dominant mutations in sarcomere proteins, particularly myosin heavy chains (MHC), are primary genetic drivers of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy.
- Understanding the genetic basis and developing targeted therapies for HCM is crucial due to its significant morbidity and mortality.
Purpose of the Study:
- To investigate the efficacy of RNA interference (RNAi) in selectively silencing the expression of a specific HCM-causing cardiac myosin heavy chain (MHC) gene mutation (Myh6 R403Q) in a mouse model.
- To determine if partial silencing of the mutant transcript can prevent the development of pathological cardiac manifestations in vivo.
Main Methods:
- Adeno-associated virus (AAV) vector was used to deliver an RNA interference (RNAi) cassette targeting the Myh6 R403Q mutation in mice.
- Mice with the cardiac MHC gene (Myh6) R403Q mutation were monitored for the development of hypertrophy and myocardial fibrosis for at least 6 months post-transduction.
Main Results:
- Selective silencing of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation was achieved using RNAi delivered by an AAV vector.
- RNAi-transduced MHC(403/+) mice did not develop hypertrophy or myocardial fibrosis, key pathological features of HCM, over a 6-month observation period.
- A modest reduction (25%) in mutant transcript levels was sufficient to inhibit HCM pathogenesis.
Conclusions:
- Partial silencing of mutant transcripts, even by 25%, can effectively inhibit the development of hypertrophic cardiomyopathy.
- The variable clinical presentation of HCM may be linked to allele-specific expression levels of the mutant gene.
- RNAi-mediated partial silencing of mutant sarcomere protein genes represents a promising therapeutic avenue for treating genetic cardiomyopathies like HCM.
Abstract:
Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.
