An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models
| Autor: | Henrik Frydenlund Hansen, Maria A. Graziewicz, Jennifer Roberts, Ryszard Kole, Henrik Ørum, Peter Sazani, Brian K. Buckley, Le Shara M. Fulton, Teresa K. Tarrant |
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| Rok vydání: | 2008 |
| Předmět: |
Oligonucleotides
Arthritis Mice Inbred Strains Biology Article Etanercept Cell Line Hepatitis 03 medical and health sciences Exon Mice 0302 clinical medicine Downregulation and upregulation Drug Discovery medicine Genetics Animals Humans Receptors Tumor Necrosis Factor Type II Locked nucleic acid Receptor Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences Tumor Necrosis Factor-alpha medicine.disease Molecular biology Arthritis Experimental 3. Good health Up-Regulation Disease Models Animal 030220 oncology & carcinogenesis RNA splicing Cancer research Hepatocytes Molecular Medicine Tumor necrosis factor alpha RNA Splice Sites medicine.drug |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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