AN ICAM-1 ANTISENSE OLIGONUCLEOTIDE PREVENTS AND REVERSES DEXTRAN SULFATE SODIUM-INDUCED COLITIS IN MICE

Mice treated p.o. with 5% dextran sodium sulfate develop a mild to mod erate colitis characterized by focal areas of inflammation and crypt a bscesses. Immunohistological analysis of colons from dextran sodium su lfate-treated mice revealed an increased expression of intercellular a dhesion molecule 1 (ICAM-1) and infiltration of lymphocyte function an tigen I-positive cells. A murine-specific antisense oligonucleotide, I SIS 3082, was used to determine the role of ICAM-1 expression in the d evelopment of colitis. Prophylactic treatment of dextran sodium sulfat e-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 leuk ocytes were observed in colons of animals treated with 1 mg/kg ISIS 30 82. Scrambled control oligonucleotides failed to modify the course of the disease. The ICAM-1 oligonucleotide also diminished the clinical s everity of colitis in mice with established colitis. The toxicity of I SIS 3082 was assessed in normal CD-1 mice by administering the oligonu cleotide intravenously every other day for 2 weeks. At pharmacological ly relevant doses of ISIS 3082 (1 and 10 mg/kg), there were no signs o f toxicity with respect to body and organ weights, clinical chemistry or hematology. At a dose of oligonucleotide 20- to 100-fold greater th an maximal pharmacological doses, the oligonucleotide produced an incr ease in liver and spleen weights; a mild chronic inflammation in liver , lung and lymph nodes; monocytosis and an elevation of serum liver tr ansaminases. These data suggest that an antisense oligonucleotide that reduces ICAM-1 expression could be effective in the therapy of inflam matory bowel disease in humans and that such an oligonucleotide would be safe at pharmacologically relevant doses.