Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides

Mol Ther Nucleic Acids. 2020 Mar 6;19:1290-1298. doi: 10.1016/j.omtn.2020.01.012. Epub 2020 Jan 21.


Hundreds of dominant-negative myosin mutations have been identified that lead to hypertrophic cardiomyopathy, and the biomechanical link between mutation and disease is heterogeneous across this patient population. To increase the therapeutic feasibility of treating this diverse genetic population, we investigated the ability of locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) to selectively knock down mutant myosin transcripts by targeting single-nucleotide polymorphisms (SNPs) that were found to be common in the myosin heavy chain 7 (MYH7) gene. We identified three SNPs in MYH7 and designed ASO libraries to selectively target either the reference or alternate MYH7 sequence. We identified ASOs that selectively knocked down either the reference or alternate allele at all three SNP regions. We also show allele-selective knockdown in a mouse model that was humanized on one allele. These results suggest that SNP-targeting ASOs are a promising therapeutic modality for treating cardiac pathology.

Keywords: RNA degradation; antisense oligonucleotides; cardiac hypertrophy; cardiomyopathy; myosin; nucleic acid.