An Endogenous TNF-α Antagonist Induced by Splice-switching Oligonucleotides Reduces Inflammation in Hepatitis and Arthritis Mouse Models.
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.
Ercole Biotech, Inc., Research Triangle Park, North Carolina, USA.
Maria A
MA
Graziewicz
Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Teresa K
TK
Tarrant
Ercole Biotech, Inc., Research Triangle Park, North Carolina, USA.
Brian
B
Buckley
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jennifer
J
Roberts
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
LeShara
L
Fulton
Santaris Pharma, Hørsholm, Denmark.
Henrik
H
Hansen
Santaris Pharma, Hørsholm, Denmark.
Henrik
H
Ørum
Ercole Biotech, Inc., Research Triangle Park, North Carolina, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Ryszard
R
Kole
Ercole Biotech, Inc., Research Triangle Park, North Carolina, USA. Electronic address: sazani@ercolebiotech.com.
Peter
P
Sazani