Intestinal inflammation can occur in a number of pathologies, perhaps the most serious of which is inflammatory bowel disease (IBD). IBD is an umbrella term used to describe two distinct clinical conditions, ulcerative colitis and Crohn's disease, both of which are chronic digestive diseases resulting from an abnormal immune system response to stimuli in the digestive tract. Ulcerative colitis primarily occurs in the colon and causes inflammation in the upper layers of the large intestine, while Crohn's disease usually appears in the small intestine and causes inflammation deeper within the wall of the intestine. IBD usually begins at a young age, is medically incurable, often requires surgery, and can recur over a lifetime. The cause of IBD is unknown although it is generally considered that a genetic predisposition contributes to an unregulated intestinal immune response to an environmental, dietary, or infectious agent. In 2001, the number of prevalent cases of IBD has been estimated to have totaled over 1.5 million in the major pharmaceutical markets. Currently in excess of $0.5 billion, IBD related sales have been forcasted to increase by 3-10% each year for the next 5 years. Current treatment options are sub-optimal and the present focus is on the identification of inflammatory mediators involved in IBD. A greater understanding of inflammatory pathways and new "biologic agents" that will emerge from this knowledge will expand the IBD market and provide improved options for the patient.

One molecular target that has received considerable attention for a range of inflammatory diseases is TNF-alpha. For example, Etanercept (Enbrel) is a decoy receptor for TNF-alpha that has been launched for the treatment of rheumatoid arthritis. Likewise, Infliximab is a chimeric MAb against TNF-Alpha launched for the treatment of Crohn's disease and rheumatoid arthritis. An alternative approach to the blockade of TNF-alpha is through the use of antisense technology to prevent its production. Hence ISIS has developed ISIS-104838, a 2nd-generation antisense TNF-alpha inhibitor, which is in phase II trials for the treatment of rheumatoid arthritis and psoriasis. As with rheumatoid arthritis and psoriasis, TNF-alpha is also a key cytokine involved in the pathogenesis of IBD. Reflecting this role of TNF-alpha, ISIS have evaluated a second-generation antisense oligonucleotide (ISIS 25302) specific for murine TNF-alpha in two distinct models of gut inflammation. ISIS 25302 decreased TNF-alpha mRNA in a dose- and sequence-dependent manner in vitro in the mouse macrophage cell line P388D1. ISIS 25302 also significantly reduced disease activity index scores in mice with both an acute and a chronic form of dextran sodium sulfate-induced colitis. Likewise histopathological scores were reduced in interleukin-10-deficient mice. This was accompanied by reductions in both the basal and lipopolysaccharide-stimulated secretion of TNF-alpha and interferon-gamma in colonic organ cultures from IL-10 -/- mice. Importantly, in this model, efficacy was obtained with both a prophylactic treatment regimen or a therapeutic dosing protocol begun after colitis was already present. In both the dextran sodium sulfate and IL-10 -/- models, scrambled and mismatch control oligonucleotides were largely without effect, suggesting that ISIS 25302 was exerting its effects through a sequence-dependent antisense mechanism. These data establish a proof of concept for further testing of molecules such as ISIS 25302 in IBD patients.

Of interest this study also reported that ISIS 25302 reduced TNF-alpha mRNA in whole adipose tissue and in macrophages isolated from the adipose tissue of db/db mice, a strain of mouse with constitutively high expression of TNF-alpha and which is used in the development of treatments of diabetes. TNF-alpha has been implicated in the development of insulin resistance and indeed Etanercept is in phase I, while Humicade (a second TNF-alpha antibody) is in phase II development for the treatment of diabetes. The effects of ISIS 25302 in models of diabetes are therefore eagerly awaited.

Entry date January, 2003

Adapted from Myers et al, J Pharmacol Exp Ther 2003 Jan;304(1):411-24 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.