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An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models.

Publication ,  Journal Article
Graziewicz, MA; Tarrant, TK; Buckley, B; Roberts, J; Fulton, L; Hansen, H; Ørum, H; Kole, R; Sazani, P
Published in: Mol Ther
July 2008

Tumor necrosis factor-alpha (TNF-alpha) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti-TNF-alpha drugs such as etanercept are effective treatments. Splice-switching oligonucleotides (SSOs) are a new class of drugs designed to induce therapeutically favorable splice variants of targeted genes. In this work, we used locked nucleic acid (LNA)-based SSOs to modulate splicing of TNF receptor 2 (TNFR2) pre-mRNA. The SSO induced skipping of TNFR2 exon 7, which codes the transmembrane domain (TM), switching endogenous expression from the membrane-bound, functional form to a soluble, secreted form (Delta7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-alpha, and altered disease in two mouse models: TNF-alpha-induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF-alpha antagonist by oligonucleotide-induced splicing modulation.

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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

July 2008

Volume

16

Issue

7

Start / End Page

1316 / 1322

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Necrosis Factor-alpha
  • Receptors, Tumor Necrosis Factor, Type II
  • RNA Splice Sites
  • Oligonucleotides
  • Mice, Inbred Strains
  • Mice
  • Humans
  • Hepatocytes
  • Hepatitis
 

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Graziewicz, M. A., Tarrant, T. K., Buckley, B., Roberts, J., Fulton, L., Hansen, H., … Sazani, P. (2008). An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models. Mol Ther, 16(7), 1316–1322. https://doi.org/10.1038/mt.2008.85
Graziewicz, Maria A., Teresa K. Tarrant, Brian Buckley, Jennifer Roberts, LeShara Fulton, Henrik Hansen, Henrik Ørum, Ryszard Kole, and Peter Sazani. “An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models.Mol Ther 16, no. 7 (July 2008): 1316–22. https://doi.org/10.1038/mt.2008.85.
Graziewicz MA, Tarrant TK, Buckley B, Roberts J, Fulton L, Hansen H, et al. An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models. Mol Ther. 2008 Jul;16(7):1316–22.
Graziewicz, Maria A., et al. “An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models.Mol Ther, vol. 16, no. 7, July 2008, pp. 1316–22. Pubmed, doi:10.1038/mt.2008.85.
Graziewicz MA, Tarrant TK, Buckley B, Roberts J, Fulton L, Hansen H, Ørum H, Kole R, Sazani P. An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models. Mol Ther. 2008 Jul;16(7):1316–1322.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

July 2008

Volume

16

Issue

7

Start / End Page

1316 / 1322

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Necrosis Factor-alpha
  • Receptors, Tumor Necrosis Factor, Type II
  • RNA Splice Sites
  • Oligonucleotides
  • Mice, Inbred Strains
  • Mice
  • Humans
  • Hepatocytes
  • Hepatitis