ArticleNucleic acids research2018
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.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 103 citations in OpenAlex.
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- The splice of life: an isoform-centric view of disease, technology, and therapeutics.The Journal of clinical investigation · 2026Review
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- Single-base 2'OMe-modified LNA and MOE gapmers selectively silenceMolecular therapy. Nucleic acids · 2026Article
- Advances in antisense oligonucleotide treatment for cancer.Japanese journal of clinical oncology · 2026Review
- Development and Validation of an Ion-Pair Reverse-Phase High-Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry Method for Determination of Purity of Nusinersen for Quality Control of Drug Substance or Drug Product.International journal of molecular sciences · 2026Article
- Integrating transcriptomics and proteomics to assess antisense oligonucleotide safety and efficacy: a time-resolved approach.NAR molecular medicine · 2026Article
- Unraveling and controlling late-onset neurotoxicity of antisense oligonucleotides through strategic chemical modifications.Molecular therapy. Nucleic acids · 2025Article
- Synthesis of 4'-C-α-Aminoethoxy-2'-O-Methyl-5-Methyl- and 5-Propynyl-Uridine Phosphoramidites for Structurally Optimized Antisense Oligonucleotides.Current protocols · 2025Article
- RNA chemistry and therapeutics.Nature reviews. Drug discovery · 2025Review
- Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo.Nature communications · 2025Article
- Aptamer-based approaches in leukemia: a paradigm shift in targeted therapy.Clinical and experimental medicine · 2025Review
- AmNA-Modified Antisense Oligonucleotide Targeting MCM8 as a Cancer-Specific Chemosensitizer for Platinum Compounds.Cancer science · 2025Article
- Synthesis and Application of 4'-Molecules (Basel, Switzerland) · 2025Article
- Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.Translational neurodegeneration · 2025Review
- Evolution of antisense oligonucleotides: navigating nucleic acid chemistry and delivery challenges.Expert opinion on drug discovery · 2025Review
- The Roles, Mechanisms, and Clinical Significance of Long Non-coding RNA MSC-AS1 in Cancer.Mini reviews in medicinal chemistry · 2025Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We reported previously that a 2' fluoro-modified (2' F) phosphorothioate (PS) antisense oligonucleotides (ASOs) with 5-10-5 gapmer configuration interacted with proteins from Drosophila behavior/human splicing (DBHS) family with higher affinity than PS-ASOs modified with 2'-O-(2-methoxyethyl) (2' MOE) or 2',4'-constrained 2'-O-ethyl (cEt) did. Rapid degradation of these proteins and cytotoxicity were observed in cells treated with 2' F PS-ASO. Here, we report that 2' F gapmer PS-ASOs of different sequences caused reduction in levels of DBHS proteins and hepatotoxicity in mice. 2' F PS-ASOs induced activation of the P53 pathway and downregulation of metabolic pathways. Altered levels of RNA and protein markers for hepatotoxicity, liver necrosis, and apoptosis were observed as early as 24 to 48 hours after a single administration of the 2' F PS-ASO. The observed effects were not likely due to the hybridization-dependent RNase H1 cleavage of on- or potential off-target RNAs, or due to potential toxicity of 2' F nucleoside metabolites. Instead, we found that 2' F PS-ASO associated with more intra-cellular proteins including proteins from DBHS family. Our results suggest that protein-binding correlates positively with the 2' F modification-dependent loss of DBHS proteins and the toxicity of gapmer 2' F PS-ASO in vivo.
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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.