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2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.

Publication ,  Journal Article
Lee, Y; Urban, JH; Xu, L; Sullenger, BA; Lee, J
Published in: Nucleic Acid Ther
June 2016

Although the use of RNAs has enormous therapeutic potential, these RNA-based therapies can trigger unwanted inflammatory responses by the activation of pattern recognition receptors (PRRs) and cause harmful side effects. In contrast, the immune activation by therapeutic RNAs can be advantageous for treating cancers. Thus, the immunogenicity of therapeutic RNAs should be deliberately controlled depending on the therapeutic applications of RNAs. In this study, we demonstrated that RNAs containing 2'fluoro (2'F) pyrimidines differentially controlled the activation of PRRs. The activity of RNAs that stimulate toll-like receptors 3 and 7 was abrogated by the incorporation of 2'F pyrimidine. By contrast, incorporation of 2'F pyrimidines enhanced the activity of retinoic acid-inducible gene 1-stimulating RNAs. Furthermore, we found that transfection with RNAs containing 2'F pyrimidine and 5' triphosphate (5'ppp) increased cell death and interferon-β expression in human cancer cells compared with transfection with 2'hydroxyl 5'ppp RNAs, whereas RNAs containing 2'O-methyl pyrimidine and 5'ppp completely abolished the induction of cell death and cytokine expression in the cells. Our findings suggest that incorporation of 2'F and 2'O-methyl nucleosides is a facile approach to differentially control the ability of therapeutic RNAs to activate or limit immune and inflammatory responses depending on therapeutic applications.

Duke Scholars

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Published In

Nucleic Acid Ther

DOI

EISSN

2159-3345

Publication Date

June 2016

Volume

26

Issue

3

Start / End Page

173 / 182

Location

United States

Related Subject Headings

  • Toll-Like Receptor 3
  • Receptors, Pattern Recognition
  • RNA
  • Nucleic Acid Conformation
  • Humans
  • Gene Expression Regulation
  • Floxuridine
  • Cytokines
  • Cell Death
 

Citation

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Lee, Y., Urban, J. H., Xu, L., Sullenger, B. A., & Lee, J. (2016). 2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors. Nucleic Acid Ther, 26(3), 173–182. https://doi.org/10.1089/nat.2015.0575
Lee, Youngju, Johannes H. Urban, Li Xu, Bruce A. Sullenger, and Jaewoo Lee. “2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.Nucleic Acid Ther 26, no. 3 (June 2016): 173–82. https://doi.org/10.1089/nat.2015.0575.
Lee Y, Urban JH, Xu L, Sullenger BA, Lee J. 2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors. Nucleic Acid Ther. 2016 Jun;26(3):173–82.
Lee, Youngju, et al. “2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.Nucleic Acid Ther, vol. 26, no. 3, June 2016, pp. 173–82. Pubmed, doi:10.1089/nat.2015.0575.
Lee Y, Urban JH, Xu L, Sullenger BA, Lee J. 2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors. Nucleic Acid Ther. 2016 Jun;26(3):173–182.
Journal cover image

Published In

Nucleic Acid Ther

DOI

EISSN

2159-3345

Publication Date

June 2016

Volume

26

Issue

3

Start / End Page

173 / 182

Location

United States

Related Subject Headings

  • Toll-Like Receptor 3
  • Receptors, Pattern Recognition
  • RNA
  • Nucleic Acid Conformation
  • Humans
  • Gene Expression Regulation
  • Floxuridine
  • Cytokines
  • Cell Death