Epigenetic silencing of pathogenetic allele accompanied by normal allele elevation for treatment of hypertrophy cardiomyopathy
Epigenetic treatment of autosomal dominant diseases requires precise targeting of pathogenic allele. We developed an allele-specific epigenetic editing method ("EpiAllele") for silencing pathogenic allele, but found surprisingly elevated expression of the normal allele, with the total expression of targeted gene unchanged. In a hypertrophic cardiomyopathy (HCM) model mice with gain-of-function Myh6 mutation, Epi-Allele achieved epigenetic silencing of mutated Myh6 allele together with elevated expression of normal allele, alleviating HCM cardiac phenotypes. In HCM patient iPSC-derived cardiomyocytes carrying MYH7 mutation, we found the same Epi-Allele-induced reshaping of pathogenic vs. normal allele expression. Finally, we showed that Epi-Allele reshaping of allele expression may result from a redistribution of transcription factors from pathogenic to normal alleles. Thus, EpiAllele offers an allele-specific therapeutic approach for treating autosomal dominant diseases via reducing mutated proteins while restoring normal proteins.