Amelioration of Chronic and Spontaneous Intestinal Inflammation with an Antisense Oligonucleotide (ISIS 9125) to Intracellular Adhesion Molecule-1 in the HLA-B27/β2 Microglobulin Transgenic Rat Model

Abstract

Adhesion molecules are known to be an important part of leukocyte migration and extravasation in both homeostatic and inflammatory conditions. Intracellular adhesion molecule-1 (ICAM-1 or CD54) is constitutively expressed on endothelial cells and is up-regulated during acute and chronic inflammation. We investigated the efficacy and consequences of interfering with CD54 after administration of an antisense oligonucleotide to ICAM-1 (CD54) in the transgenic HLA-B27/␤2 microglobulin rat model. One hundred percent of the HLA-B27 transgene ϩ animals will spontaneously develop chronic inflammation (some more severely than others) in the gastric mucosa, cecum, and colon. We carried out two studies, i.p. injection and rectal administration of antisense. Following i.p. and rectal treatment, there were significant decreases in colonic mucosal wall thickness, histologic inflammation, CD54 expression in the colon and peripheral blood, and the percentage of colon weight per end body weight. Furthermore, decreased expression of CD49d, CD18, and tumor necrosis factor-␣ was observed in antisense treated rats. Therefore, the HLA-B27 transgenic model of spontaneous and chronic inflammatory bowel disease, which has increased expression of adhesion molecules, responds to both routes of administration of ICAM-1 antisense oligonucleotides. These studies support the regulatory role of adhesion molecules in chronic intestinal inflammation, the need for an understanding of how the route of drug delivery can alter the dose and area affected, and finally the role of antisense oligonucleotides as a therapeutic modality in chronic spontaneous inflammatory bowel diseases.

NF-κB Activation Precedes Increases in mRNA Encoding Neurokinin-1 Receptor, Proinflammatory Cytokines, and Adhesion Molecules in Dextran Sulfate Sodium–Induced Colitis in Rats

“…The early-increased transcripts, ICAM-1 and CINC-1, encode for proteins involved in initiating inflammation via recruitment and retention of leucocytes and neutrophils (25,26). The importance of ICAM-1 in IBD has been well characterized (45,46). ICAM-1 is constitutively expressed on the surface of endothelial cells, and in CUC, ICAM-1 levels increase concomitantly with inflammation (47,48).…”

Transport of nanocarriers across gastrointestinal epithelial cells by a new transcellular route induced by targeting ICAM-1

“…This is useful for drug delivery to the GI epithelium for prophylactic interventions, or across this barrier for delivery to other sites. ICAM-1 expression is high in colorectal carcinoma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, bacterial infections, and other conditions [15, 39–41]. Hence, ICAM-1 targeting also holds promise for therapeutic applications for these maladies.…”

An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule‐1, in the treatment of chronic, unremitting pouchitis

“…Our open‐label, proof‐of‐concept trial explored the potential therapeutic benefit of ISIS 2302 in patients with chronic, unremitting pouchitis. A 60‐mL, 240‐mg enema formulation of ISIS 2302 was selected on the basis of animal studies, which predicted local tissue concentrations within the range shown to be effective in animal pharmacology models of inflammatory bowel disease 6 . A 6‐week duration of therapy was chosen on the basis of ongoing clinical trials in patients with active ulcerative colitis.…”