An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models.
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.
Graziewicz, MA; Tarrant, TK; Buckley, B; Roberts, J; Fulton, L; Hansen, H; Ørum, H; Kole, R; Sazani, P
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