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 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.
Bennett
C F
CF
ISIS Pharmaceuticals, Carlsbad, California 92008, USA.
Kornbrust
D
D
Henry
S
S
Stecker
K
K
Howard
R
R
Cooper
S
S
Dutson
S
S
Hall
W
W
Jacoby
H I
HI
D000818:Animals; D001483:Base Sequence; D001772:Blood Cell Count / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis / Q000096:biosynthesis; D016177:Macrophage-1 Antigen / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use* / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D012727:Sex Characteristics; D013873:Thionucleotides
D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; D016264:Dextran Sulfate