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

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Abstract

Tumor necrosis factor-α (TNF-α) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti-TNF-α 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 (Δ7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-α, and altered disease in two mouse models: TNF-α-induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF-α antagonist by oligonucleotide-induced splicing modulation.

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Graziewicz, M. A., Tarrant, T. K., Buckley, B., Roberts, J., Fulton, L. S., Hansen, H., … Sazani, P. (2008). An endogenous TNF-α antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models. Molecular Therapy, 16(7), 1316–1322. https://doi.org/10.1038/mt.2008.85

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