ArticleThe Journal of experimental medicine2015
Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators.
Article in The Journal of experimental medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
What it found
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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.
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Who cites it
53 citing papers in PubMed, 107 citations in OpenAlex.
- Meta-analysis of adverse events in clinical studies with antisense oligonucleotide therapies.Molecular therapy. Nucleic acids · 2026Review
- Heteroduplex oligonucleotide technology boosts gene knockdown in cardiac and skeletal muscles.Nucleic acids research · 2026Article
- Developing antisense oligomer biotics "asobiotics" as precision antibacterials: designs, strategies, and considerations for future success.FEMS microbiology reviews · 2026Review
- PSCA-directed nanosized bio-immune conjugates (NANO:BICs) enable selective uptake of TLR9 agonists in bladder cancer cells.Frontiers in oncology · 2026Article
- Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems.Pharmacological reviews · 2025Review
- Cellular immune changes during severe antisense oligonucleotide-associated thrombocytopenia in a nonhuman primate model.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines.Signal transduction and targeted therapy · 2025Review
- Competing endogenous RNAs network dysregulation in oral cancer: a multifaceted perspective on crosstalk and competition.Cancer cell international · 2024Review
- Chitosan siRNA Nanoparticles Produce Significant Non-Toxic Functional Gene Silencing in Kidney Cortices.Polymers · 2024Article
- Physiological platelet aggregation assay to mitigate drug-induced thrombocytopenia using a microphysiological system.Scientific reports · 2024Article
- Frameworks for transformational breakthroughs in RNA-based medicines.Nature reviews. Drug discovery · 2024Review
- Post-prandial analysis of fluctuations in the platelet count and platelet function in patients with the familial chylomicronemia syndrome.Orphanet journal of rare diseases · 2023Article
- Cholesterol Lowering Biotechnological Strategies: From Monoclonal Antibodies to Antisense Therapies. A Pre-Clinical Perspective Review.Cardiovascular drugs and therapy · 2023Review
- Blood Platelets in Infection: The Multiple Roles of the Platelet Signalling Machinery.International journal of molecular sciences · 2023Review
- Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny.Pharmaceutics · 2023Article
- Review
- Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.Nucleic acid therapeutics · 2023Review
- The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates.Haematologica · 2022Article
- Advantages and Disadvantages of Inclisiran: A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9-A Narrative Review.Cardiovascular therapeutics · 2022Review
Corrections and comments
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Authors and funding
16 authors at 9 institutions in 4 countries.
Funding
Abstract
Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.
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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.