A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease.
OBJECTIVE
Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn's disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohn's disease.


METHODS
Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months.


RESULTS
At the end of treatment. 47% (7 of 15) of ISIS 2302-treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302-treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302-treated patients. These findings were corroborated by significant increases in beta7 and alpha d bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period.


CONCLUSIONS
ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn's disease.
Yacyshyn
B R
BR
Division of Gastroenterology, University of Alberta, Edmonton, Canada.
Bowen-Yacyshyn
M B
MB
Jewell
L
L
Tami
J A
JA
Bennett
C F
CF
Kisner
D L
DL
Shanahan
W R
WR
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004311:Double-Blind Method; D004724:Endoscopy; D005260:Female; D005767:Gastrointestinal Diseases / Q000188:drug therapy; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides; D010919:Placebos; D011795:Surveys and Questionnaires; D013873:Thionucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000305:Adrenal Cortex Hormones; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D010919:Placebos; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; C089753:alicaforsen