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Allele-selective knockdown of MYH7 using antisense oligonucleotides
Molecular Therapy - Nucleic Acids ( IF 5.919 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.omtn.2020.01.012
Brian R. Anderson; Marianne L. Jensen; Peter H. Hagedorn; Sean C. Little; Richard E. Olson; Ron Ammar; Bernadette Kienzle; John Thompson; Ivar McDonald; Stephen Mercer; Jonas Vikesaa; Bettina Nordbo; Larry Iben; Yang Cao; Joanne Natale; Greg Dalton-Kay; Angela Cacace; Bo R. Hansen; Linda J. Bristow

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 knockdown 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.
更新日期:2020-01-21

 

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