ArticleNature biotechnology2019
Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index.
Article in Nature biotechnology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 212 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
212 citing papers in PubMed, 315 citations in OpenAlex.
- Gapmers targeting conserved SARS-CoV-2 single-stranded regions reduce viral load and reshape inflammatory macrophage responses.iScience · 2026Article
- Chemically stabilized long antisense oligonucleotides perturb RNA exosome function.Nucleic acids research · 2026Article
- Recent advances in the regulation of CD47 by non-coding RNAs and its therapeutic potential in cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- SafeSense: An open-access safety atlas for antisense oligonucleotides adverse events in human.Molecular therapy. Nucleic acids · 2026Article
- Targeting lncRNAs to Overcome Cancer Therapy Resistance: Advances in RNA Therapeutics and Delivery Strategies.Cancers · 2026Review
- Single-residue engineering of Klenow fragment enables broad acceptance of chemically modified nucleotides.Nucleic acids research · 2026Article
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- Antibody-oligonucleotide conjugates: an emerging modality for precision RNA therapeutics.Antibody therapeutics · 2026Review
- Interaction between lncRNAs and RNA binding proteins, and their potential as drug targets in the therapy of liver cancer (Review).Biomedical reports · 2026Review
- The Versatile Applications of Antisense Oligonucleotides in Modern Medicine.International journal of molecular sciences · 2026Review
- ClinASO: An open-source platform for rapid drug discovery of gapmer antisense oligonucleotides.Molecular therapy. Nucleic acids · 2026Article
- Single-base 2'OMe-modified LNA and MOE gapmers selectively silenceMolecular therapy. Nucleic acids · 2026Article
- Therapeutic siRNA: Mechanisms, challenges, strategies, and clinical translation.Chinese medical journal · 2026Review
- TopCas: Topology-Gated Cas12a via DNA-RNA Chimeric Circular crRNA for Amplification-Free Nucleic Acid Detection and Conditional Gene Editing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Nucleic Acid Therapeutics for "Undruggable" Cancer Targets: Mechanisms, Challenges, and Prospects.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- RNA Therapeutics Targeting Skeletal Muscle: Emerging Antisense and Gene-Modifying Strategies.Biomolecules · 2026Review
- Enhanced splicing modulation by NMA-modified antisense oligonucleotides.Nucleic acids research · 2026Article
- Addressing the needs of nano-rare patients: the n-Lorem experience.Nucleic acids research · 2026Review
- Synthesis and properties of l-RSC chemical biology · 2026Article
- Advances in antisense oligonucleotide treatment for cancer.Japanese journal of clinical oncology · 2026Review
152 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 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The molecular mechanisms of toxicity of chemically modified phosphorothioate antisense oligonucleotides (PS-ASOs) are not fully understood. Here, we report that toxic gapmer PS-ASOs containing modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2'-O-methoxyethyl (2'-MOE) bind many cellular proteins with high avidity, altering their function, localization and stability. We show that RNase H1-dependent delocalization of paraspeckle proteins to nucleoli is an early event in PS-ASO toxicity, followed by nucleolar stress, p53 activation and apoptotic cell death. Introduction of a single 2'-O-methyl (2'-OMe) modification at gap position 2 reduced protein-binding, substantially decreasing hepatotoxicity and improving the therapeutic index with minimal impairment of antisense activity. We validated the ability of this modification to generally mitigate PS-ASO toxicity with more than 300 sequences. Our findings will guide the design of PS-ASOs with optimal therapeutic profiles.
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.