title: An endogenous TNF-alpha antagonist induced by splice-switching oligonucleotides reduces inflammation in hepatitis and arthritis mouse models.
abstract: 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.
authors.affiliation: Ercole Biotech, Inc., Research Triangle Park, North Carolina 27709, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Graziewicz
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Tarrant
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.forename: Jennifer
authors.initials: J
authors.lastname: Roberts
authors.forename: LeShara
authors.initials: L
authors.lastname: Fulton
authors.forename: Henrik
authors.initials: H
authors.lastname: Hansen
authors.forename: Henrik
authors.initials: H
authors.lastname: Ørum
authors.forename: Ryszard
authors.initials: R
authors.lastname: Kole
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002460:Cell Line; D004195:Disease Models, Animal; D006505:Hepatitis / Q000188:drug therapy*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009841:Oligonucleotides / Q000627:therapeutic use*; D022821:RNA Splice Sites; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D009841:Oligonucleotides; D022821:RNA Splice Sites; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C477371:locked nucleic acid