1. ¹Ercole Biotech, Inc., Research Triangle Park, North Carolina, USA
2. ²Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
3. ³Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
4. ⁴Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
5. ⁵Santaris Pharma, Hørsholm, Denmark

Correspondence: Peter Sazani, Ercole Biotech, Inc., PO Box 12295, Research Triangle Park, Durham, North Carolina 27709, USA. E-mail: sazani@ercolebiotech.com

Received 4 February 2008; Accepted 2 April 2008; Published online 6 May 2008.

Abstract

Tumor necrosis factor- (TNF-) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti–TNF- 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 (7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-, and altered disease in two mouse models: TNF--induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF- antagonist by oligonucleotide-induced splicing modulation.