ArticlePloS one2014
Defining the factors that contribute to on-target specificity of antisense oligonucleotides.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 48 citations in OpenAlex.
- Exploring the Potential of PhosphoramideACS omega · 2026Article
- Chemical Modifications in Nucleic Acid Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Drug Discovery Perspectives of Antisense Oligonucleotides.Biomolecules & therapeutics · 2023Review
- Nonviral delivery systems for antisense oligonucleotide therapeutics.Biomaterials research · 2022Review
- Expansion of the RNAStructuromeDB to include secondary structural data spanning the human protein-coding transcriptome.Scientific reports · 2022Article
- RNA modifications can affect RNase H1-mediated PS-ASO activity.Molecular therapy. Nucleic acids · 2022Article
- Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy.Nature communications · 2022Article
- LncRNA-Dependent Mechanisms of Transforming Growth Factor-β: From Tissue Fibrosis to Cancer Progression.Non-coding RNA · 2022Review
- Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome.Nature structural & molecular biology · 2021Article
- Antisense technology: an overview and prospectus.Nature reviews. Drug discovery · 2021Review
- Some ASOs that bind in the coding region of mRNAs and induce RNase H1 cleavage can cause increases in the pre-mRNAs that may blunt total activity.Nucleic acids research · 2020Article
- Phosphorothioate modified oligonucleotide-protein interactions.Nucleic acids research · 2020Article
- Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands.Journal of the American Chemical Society · 2020Article
- Efficient Delivery of Antisense Oligonucleotides Using Bioreducible Lipid Nanoparticles In Vitro and In Vivo.Molecular therapy. Nucleic acids · 2020Article
- Hybridization-mediated off-target effects of splice-switching antisense oligonucleotides.Nucleic acids research · 2020Article
- COPII vesicles can affect the activity of antisense oligonucleotides by facilitating the release of oligonucleotides from endocytic pathways.Nucleic acids research · 2018Article
- Identifying and avoiding off-target effects of RNase H-dependent antisense oligonucleotides in mice.Nucleic acids research · 2018Article
- Acute hepatotoxicity of 2' fluoro-modified 5-10-5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins.Nucleic acids research · 2018Article
- Advances in therapeutic bacterial antisense biotechnology.Applied microbiology and biotechnology · 2018Review
- Translation can affect the antisense activity of RNase H1-dependent oligonucleotides targeting mRNAs.Nucleic acids research · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To better understand the factors that influence the activity and specificity of antisense oligonucleotides (ASOs), we designed a minigene encoding superoxide dismutase 1 (SOD-1) and cloned the minigene into vectors for T7 transcription of pre-mRNA and splicing in a nuclear extract or for stable integration in cells. We designed a series of ASOs that covered the entire mRNA and determined the binding affinities and activities of the ASOs in a cell-free system and in cells. The mRNA bound known RNA-binding proteins on predicted binding sites in the mRNA. The higher order structure of the mRNA had a significantly greater effect than the RNA-binding proteins on ASO binding affinities as the ASO activities in cells and in the cell-free systems were consistent. We identified several ASOs that exhibited off-target hybridization to the SOD-1 minigene mRNA in the cell-free system. Off-target hybridization occurred only at highly accessible unstructured sites in the mRNA and these interactions were inhibited by both the higher order structure of the mRNA and by RNA-binding proteins. The same off-target hybridization interactions were identified in cells that overexpress E. coli RNase H1. No off-target activity was observed for cells expressing only endogenous human RNase H1. Neither were these off-target heteroduplexes substrates for recombinant human RNase H1 under multiple-turnover kinetics suggesting that the endogenous enzyme functions under similar kinetic parameters in cells and in the cell-free system. These results provide a blueprint for design of more potent and more specific ASOs.
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