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Vol. 280, Issue 2, 988-1000, 1997
ISIS Pharmaceuticals (C.F.B., D.K., S.H., K.S., R.H., S.C.),
Carlsbad, California, Utah Biomedical Test Laboratory (S.D.), Salt Lake
City, Utah,
Pathology Associates (W.H.), Frederick, Maryland and
Discovery Research Consultants (H.I.J.) Brigantine, New Jersey
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.
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