RT Journal Article
SR Electronic
T1 Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-α in Two Murine Models of Colitis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 411
OP 424
DO 10.1124/jpet.102.040329
VO 304
IS 1
A1 Myers, Kathleen J.
A1 Murthy, Sreekant
A1 Flanigan, Anne
A1 Witchell, Donna R.
A1 Butler, Madeline
A1 Murray, Susan
A1 Siwkowski, Andrew
A1 Goodfellow, Deborah
A1 Madsen, Karen
A1 Baker, Brenda
YR 2003
UL http://jpet.aspetjournals.org/content/304/1/411.abstract
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