ArticleNucleic acids research2021
Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2'-O-methyl gapmer oligonucleotides.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 29 citations in OpenAlex.
- Bridging the antiviral gap: A BAC-based non-infectious SARS-CoV-2 replicon reveals potent antisense gapmers.Molecular therapy. Nucleic acids · 2026Article
- Multi-Omics-Guided Design and Safety Engineering of Nucleic Acid Therapeutics: From Molecular Perturbation to Predictive Toxicology and Precision Translation.Chemical biology & drug design · 2026Review
- Design and Synthesis of Novel Isoflavene TANK-Binding Kinase 1 Inhibitors With Anti-Inflammatory Activity.ChemMedChem · 2026Article
- cGAS: bridging immunity and metabolic regulation.Journal of molecular cell biology · 2026Review
- Therapeutic targeting of the cGAS-STING pathway in human disease.The Journal of clinical investigation · 2026Review
- Spotlight on cGAS-STING: role in disease pathogenesis and therapeutic potential.Molecular biomedicine · 2026Review
- Decoding Undesirable Inflammatory Responses of Nucleic Acid-Delivering Lipid Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Review
- Circular single stranded DNA potentiates non-viral gene insertion in hematopoietic stem and progenitor cells.Nature communications · 2025Article
- Chemotherapy-induced CA-repeat DNA fragments in breast cancer trigger antitumor immune responses.Nature immunology · 2025Article
- Identification and development of cGAS inhibitors and their uses to treat Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- R-loops and impaired autophagy trigger cGAS-dependent inflammation via micronuclei formation in Senataxin-deficient cells.Cellular and molecular life sciences : CMLS · 2024Article
- Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications.International journal of molecular sciences · 2024Review
- Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.Molecular neurodegeneration · 2023Review
- Understanding nucleic acid sensing and its therapeutic applications.Experimental & molecular medicine · 2023Review
- Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection.Nature communications · 2023Article
- The Crucial Roles and Research Advances of cGAS-STING Pathway in Cutaneous Disorders.Inflammation · 2023Review
- Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.Nucleic acid therapeutics · 2023Review
- Selecting Therapeutic Antisense Oligonucleotides with Gene Targeting and TLR8 Potentiating Bifunctionality.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Article
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oligonucleotide-based therapeutics have the capacity to engage with nucleic acid immune sensors to activate or block their response, but a detailed understanding of these immunomodulatory effects is currently lacking. We recently showed that 2'-O-methyl (2'OMe) gapmer antisense oligonucleotides (ASOs) exhibited sequence-dependent inhibition of sensing by the RNA sensor Toll-Like Receptor (TLR) 7. Here we discovered that 2'OMe ASOs can also display sequence-dependent inhibitory effects on two major sensors of DNA, namely cyclic GMP-AMP synthase (cGAS) and TLR9. Through a screen of 80 2'OMe ASOs and sequence mutants, we characterized key features within the 20-mer ASOs regulating cGAS and TLR9 inhibition, and identified a highly potent cGAS inhibitor. Importantly, we show that the features of ASOs inhibiting TLR9 differ from those inhibiting cGAS, with only a few sequences inhibiting both pathways. Together with our previous studies, our work reveals a complex pattern of immunomodulation where 95% of the ASOs tested inhibited at least one of TLR7, TLR9 or cGAS by ≥30%, which may confound interpretation of their in vivo functions. Our studies constitute the broadest analysis of the immunomodulatory effect of 2'OMe ASOs on nucleic acid sensing to date and will support refinement of their therapeutic development.
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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.