ArticleNucleic acids research2015
In silico and in vitro evaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization.
Article in Nucleic acids research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
72 citing papers in PubMed, 106 citations in OpenAlex.
- Silencing with precision: In silico strategies for antisense oligonucleotide engineering.Molecular biology reports · 2026Review
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- 5'-Palmitate Lipid and Internal LNA-Piperidyl Triesters Enhance the RNA Affinity and Activity of Splice-Switching Oligonucleotides.Journal of the American Chemical Society · 2026Article
- Single-base 2'OMe-modified LNA and MOE gapmers selectively silenceMolecular therapy. Nucleic acids · 2026Article
- Integrating transcriptomics and proteomics to assess antisense oligonucleotide safety and efficacy: a time-resolved approach.NAR molecular medicine · 2026Article
- Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux.International journal of oral science · 2026Article
- LncRNA Knockdown Using Gapmer Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Structural and Physicochemical Optimization of Next-Generation Antisense Oligonucleotide with BROTHERS for Mitigating Off-Target Effects.Methods in molecular biology (Clifton, N.J.) · 2026Article
- An LNA gapmer antisense oligonucleotide inhibitor of human NNMT.Molecular therapy. Nucleic acids · 2025Article
- Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells.Human molecular genetics · 2025Article
- TVAE-RNA: ensemble-based RNA secondary structure prediction via transformer variational autoencoders.Bioinformatics (Oxford, England) · 2025Article
- Article
- Antisense oligonucleotide therapies for monogenic disorders.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Review
- Chemical Modifications in Nucleic Acid Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Oligonucleotide therapies for nonalcoholic steatohepatitis.Molecular therapy. Nucleic acids · 2024Review
- Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer's disease.Molecular neurodegeneration · 2024Article
- Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments.Human mutation · 2024Review
- Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.Nature communications · 2023Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
With many safety and technical limitations partly mitigated through chemical modifications, antisense oligonucleotides (ASOs) are gaining recognition as therapeutic entities. The increase in potency realized by 'third generation chemistries' may, however, simultaneously increase affinity to unintended targets with partial sequence complementarity. However, putative hybridization-dependent off-target effects (OTEs), a risk historically regarded as low, are not being adequately investigated. Here we show an unexpectedly high OTEs confirmation rate during screening of fully phosphorothioated (PS)-LNA gapmer ASOs designed against the BACH1 transcript. We demonstrate in vitro mRNA and protein knockdown of off-targets with a wide range of mismatch (MM) and gap patterns. Furthermore, with RNase H1 activity residing within the nucleus, hybridization predicted against intronic regions of pre-mRNAs was tested and confirmed. This dramatically increased ASO-binding landscape together with relatively high potency of such interactions translates into a considerable safety concern. We show here that with base pairing-driven target recognition it is possible to predict the putative off-targets and address the liability during lead design and optimization phases. Moreover, in silico analysis performed against both primary as well as spliced transcripts will be invaluable in elucidating the mechanism behind the hepatoxicity observed with some LNA-modified gapmers.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.