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Updated: Aug 14, 2026
Murine Colitis Modeling using Dextran Sulfate Sodium (DSS)
Published on: January 19, 2010
An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice
C F Bennett1, D Kornbrust, S Henry
1ISIS Pharmaceuticals, Carlsbad, California 92008, USA.
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.
Insights
An antisense oligonucleotide targeting intercellular adhesion molecule 1 (ICAM-1) effectively reduced colitis in mice. This ICAM-1 targeting therapy showed no toxicity at relevant doses, suggesting potential for treating inflammatory bowel disease.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Dextran sodium sulfate (DSS) induces colitis in mice, characterized by inflammation and crypt abscesses.
- Increased expression of intercellular adhesion molecule 1 (ICAM-1) and leukocyte infiltration are observed in DSS-induced colitis.
- ICAM-1 plays a crucial role in the inflammatory processes associated with colitis.
Purpose of the Study:
- To investigate the therapeutic potential of a murine-specific antisense oligonucleotide (ISIS 3082) targeting ICAM-1 in a mouse model of colitis.
- To determine the role of ICAM-1 in the development and progression of DSS-induced colitis.
- To assess the safety and toxicity of ISIS 3082 at pharmacologically relevant doses.
Main Methods:
- Induction of colitis in mice using 5% dextran sodium sulfate (DSS).
- Administration of ISIS 3082 (antisense oligonucleotide targeting ICAM-1) or scrambled control oligonucleotides.
- Evaluation of clinical signs of colitis, including inflammation and crypt abscesses.
- Immunohistological analysis to assess ICAM-1 expression and leukocyte infiltration.
- Toxicological assessment of ISIS 3082 in normal mice.
Main Results:
- Prophylactic and therapeutic treatment with ISIS 3082 dose-dependently reduced clinical signs of colitis.
- ISIS 3082 treatment led to decreased ICAM-1 expression and reduced leukocyte infiltration in the colon.
- Scrambled control oligonucleotides did not affect the course of colitis.
- ISIS 3082 was found to be non-toxic in normal mice at pharmacologically relevant doses (1 and 10 mg/kg).
- Higher doses of ISIS 3082 showed mild toxicity, including increased organ weights and inflammation.
Conclusions:
- An antisense oligonucleotide targeting ICAM-1 (ISIS 3082) is effective in reducing experimental colitis in mice.
- Reduced ICAM-1 expression is critical for mitigating colitis.
- ISIS 3082 demonstrates a favorable safety profile at pharmacologically relevant doses.
- These findings suggest that ICAM-1-targeting antisense oligonucleotides hold promise for treating human inflammatory bowel disease.
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