Does an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector prevent hypertrophy and myocardial fibrosis in MHC(403/+) mice?
Allele-specific silencing of the mutant Myh6 transcript via AAV-delivered RNAi prevents the development of hypertrophic cardiomyopathy phenotypes in a mouse model.
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.
Jiang et al. (Thu,) studied this question.
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