Drug Discovery Opinion

DDO Limited – Consultancy for Biotech and Pharma

Jul 13 2009

Homing in on Crohn’s Disease

Posted by WH in News, tags: auto-immune, inflammation, target identification

Crohn’s disease is an inflammatory disease of the gastrointestinal tract that causes abdominal pain, diarrhea and vomiting. First described by Burrill Bernard Crohn and co-workers in 1932, the disease is believed to be an autoimmune disorder but the precise causes are unknown. Treatment options focus on management of acute symptoms and maintenance of remission, since no known cure is available.

Crohn himself was convinced that the disease was caused by Mycobacterium paratuberculosis (MAP), the same pathogen responsible for the related Johne’s disease in cattle. Whilst his research was unable to establish the involvement of MAP, the theory has received more attention in recent years.

New research from McGill University Health Centre (MUHC), Quebec, has established a link between the human NOD2 gene and mycobacteria. Mutations in NOD2 have been observed in approximately 25% of Crohn’s disease patients, but the nature of the effect of these mutations has not been understood. Normally, NOD2 codes for a receptor that recognises invading bacteria, triggering an immune response. The MUHC study demonstrates that the NOD2 receptor preferentially recognises a peptide, N-glycolylated peptidoglycan-derived muramyl dipeptide (MDP), which is only found in mycobacteria. When mycobacteria invade the human body, they cause an immediate and very strong immune response via the NOD2 receptor. This new discovery, published in the Journal of Experimental Medicine, associates the predisposition for Crohn’s disease with both the NOD2 mutation and the presence of mycobacteria, but researchers must still determine the precise combination of these factors to understand how the disease develops.

In a separate study, researchers from Case Western Reserve University School of Medicine have identified a novel link between ITCH, a gene known to regulate inflammation in the body and NOD2. ITCH,which encodes an E3 ubiquitin ligase, can cause a variety of inflammatory diseases when malfunctioning. The team at Case Western found that ITCH also influences NOD2-induced inflammation. These findings, to be published in the August 11^th issue of Current Biology, suggest a common pathophysiology exists between multiple inflammatory diseases. The unexpected finding of the interaction between these genes offers the possibility of new drug targets for intervention in Crohn’s disease.

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