Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides.
RNA degradation
antisense oligonucleotides
cardiac hypertrophy
cardiomyopathy
myosin
nucleic acid
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
06 Mar 2020
06 Mar 2020
Historique:
received:
26
06
2019
revised:
02
01
2020
accepted:
02
01
2020
pubmed:
26
2
2020
medline:
26
2
2020
entrez:
26
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32092825
pii: S2162-2531(20)30047-0
doi: 10.1016/j.omtn.2020.01.012
pmc: PMC7033438
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1290-1298Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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