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Vol. 304, Issue 1, 411-424, January 2003

Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-alpha in Two Murine Models of Colitis

Kathleen J. Myers, Sreekant Murthy, Anne Flanigan, Donna R. Witchell, Madeline Butler, Susan Murray, Andrew Siwkowski, Deborah Goodfellow, Karen Madsen and Brenda Baker

Isis Pharmaceuticals, Carlsbad, California (K.J.M., D.R.W., M.B., Su.M., A.S., D.G., B.B.); MCP Hahnemann University, Philadelphia, Pennsylvania (Sr.M., A.F.); and University of Alberta, Edmonton, Alberta, Canada (K.M.)

Tumor necrosis factor-alpha (TNF-alpha ) is a key cytokine involved in the pathogenesis of inflammatory bowel disease. We have developed a second-generation antisense oligonucleotide (ISIS 25302) specific for murine TNF-alpha and have evaluated this oligonucleotide in two models of gut inflammation of distinct etiology. ISIS 25302 decreased TNF-alpha mRNA in a dose- and sequence-dependent manner in vitro in the mouse macrophage cell line P388D1. It also reduced TNF-alpha mRNA in vivo, in whole adipose tissue and in macrophages isolated from the adipose tissue of db/db mice, a strain with constitutively high expression of TNF-alpha . ISIS 25302 significantly reduced disease activity index scores in mice with both an acute and a chronic form of dextran sodium sulfate (DSS)-induced colitis. It also significantly improved histopathological scores in interleukin (IL)-10-deficient mice. This was accompanied by reductions in both the basal and lipopolysaccharide-stimulated secretion of TNF-alpha and interferon-gamma in colonic organ cultures from IL-10 -/- mice. In this model, efficacy was obtained with both a prophylactic treatment regimen or a therapeutic dosing protocol begun after colitis was already present. In both the DSS and IL-10 -/- models, scrambled and mismatch control oligonucleotides were largely without effect, suggesting that ISIS 25302 was exerting its effects through a sequence-dependent antisense mechanism.

0022-3565/03/3041-0411$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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