Abstract
Mice treated p.o. with 5% dextran sodium sulfate develop a mild to moderate colitis characterized by focal areas of inflammation and crypt abscesses. Immunohistological analysis of colons from dextran sodium sulfate-treated mice revealed an increased expression of intercellular adhesion molecule 1 (ICAM-1) and infiltration of lymphocyte function antigen 1-positive cells. A murine-specific antisense oligonucleotide, ISIS 3082, was used to determine the role of ICAM-1 expression in the development of colitis. Prophylactic treatment of dextran sodium sulfate-treated mice with ISIS 3082 reduced the clinical signs of colitis in a dose-dependent manner, with maximal effects occurring at a dose of 1 mg/kg/day. Reductions in ICAM-1 immunostaining and infiltrating leukocytes were observed in colons of animals treated with 1 mg/kg ISIS 3082. Scrambled control oligonucleotides failed to modify the course of the disease. The ICAM-1 oligonucleotide also diminished the clinical severity of colitis in mice with established colitis. The toxicity of ISIS 3082 was assessed in normal CD-1 mice by administering the oligonucleotide intravenously every other day for 2 weeks. At pharmacologically relevant doses of ISIS 3082 (1 and 10 mg/kg), there were no signs of toxicity with respect to body and organ weights, clinical chemistry or hematology. At a dose of oligonucleotide 20- to 100-fold greater than maximal pharmacological doses, the oligonucleotide produced an increase in liver and spleen weights; a mild chronic inflammation in liver, lung and lymph nodes; monocytosis and an elevation of serum liver transaminases. These data suggest that an antisense oligonucleotide that reduces ICAM-1 expression could be effective in the therapy of inflammatory bowel disease in humans and that such an oligonucleotide would be safe at pharmacologically relevant doses.
Footnotes
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Send reprint requests to: C. Frank Bennett, Ph.D., Department of Molecular Pharmacology, ISIS Pharmaceuticals Inc., 2292 Faraday Ave., Carlsbad, CA 92008
- Abbreviations:
- AST
- aspartate aminotransferase
- ALT
- alanine aminotransferase
- BSA
- bovine serum albumin
- DAI
- disease activity index
- DSS
- dextran sodium sulfate
- IBD
- inflammatory bowel disease
- ICAM-1
- intercellular adhesion molecule 1
- LFA-1
- lymphocyte function antigen 1
- NMR
- nuclear magnetic resonance
- TGFβ
- transforming growth factor β
- VCAM-1
- vascular cell adhesion molecule 1
- Received September 13, 1995.
- Accepted October 15, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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