Journal article
Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2′-O-methyl gapmer oligonucleotides
Nucleic Acids Research, Vol.49(11), pp.6082-6099
2021
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.
Details
- Title
- Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2′-O-methyl gapmer oligonucleotides
- Authors/Creators
- R. Valentin (Author/Creator) - Hudson Institute of Medical ResearchC. Wong (Author/Creator) - Hudson Institute of Medical ResearchA.S. Alharbi (Author/Creator) - Hudson Institute of Medical ResearchS. Pradeloux (Author/Creator) - Hudson Institute of Medical ResearchM.P. Morros (Author/Creator) - Hudson Institute of Medical ResearchK.A. Lennox (Author/Creator) - Integrated DNA Technologies (United States)J.I. Ellyard (Author/Creator) - Australian National UniversityA.J. Garcin (Author/Creator) - Hudson Institute of Medical ResearchT.R. Ullah (Author/Creator) - Hudson Institute of Medical ResearchG.D. Kusuma (Author/Creator) - Monash UniversityG. Pépin (Author/Creator) - Hudson Institute of Medical ResearchH-M Li (Author/Creator) - Hudson Institute of Medical ResearchJ.S. Pearson (Author/Creator) - Hudson Institute of Medical ResearchJ. Ferrand (Author/Creator) - Hudson Institute of Medical ResearchR. Lim (Author/Creator) - Australian Regenerative Medicine InstituteR.N. Veedu (Author/Creator) - Murdoch UniversityE.F. Morand (Author/Creator) - Monash UniversityC.G. Vinuesa (Author/Creator) - Australian National UniversityM.A. Behlke (Author/Creator) - Integrated DNA Technologies (United States)M.P. Gantier (Author/Creator) - Hudson Institute of Medical Research
- Publication Details
- Nucleic Acids Research, Vol.49(11), pp.6082-6099
- Publisher
- Oxford University Press
- Identifiers
- 991005543600307891
- Copyright
- © 2021 The Authors.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
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- Citation topics
- 1 Clinical & Life Sciences
- 1.6 Immunology
- 1.6.609 Toll-like Receptors
- Web Of Science research areas
- Biochemistry & Molecular Biology
- ESI research areas
- Biology & Biochemistry