PT  - JOURNAL ARTICLE
AU  - Myers, Kathleen J.
AU  - Murthy, Sreekant
AU  - Flanigan, Anne
AU  - Witchell, Donna R.
AU  - Butler, Madeline
AU  - Murray, Susan
AU  - Siwkowski, Andrew
AU  - Goodfellow, Deborah
AU  - Madsen, Karen
AU  - Baker, Brenda
TI  - Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-α in Two Murine Models of Colitis
AID  - 10.1124/jpet.102.040329
DP  - 2003 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 411--424
VI  - 304
IP  - 1
4099  - http://jpet.aspetjournals.org/content/304/1/411.short
4100  - http://jpet.aspetjournals.org/content/304/1/411.full
SO  - J Pharmacol Exp Ther2003 Jan 01; 304
AB  - Tumor necrosis factor-α (TNF-α) 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-α and have evaluated this oligonucleotide in two models of gut inflammation of distinct etiology. ISIS 25302 decreased TNF-α mRNA in a dose- and sequence-dependent manner in vitro in the mouse macrophage cell line P388D1. It also reduced TNF-α 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-α. 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-α and interferon-γ 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. The American Society for Pharmacology and Experimental Therapeutics