Lay Summary

Proposal No. IBD-0241R2
Principal Investigator: Gerhard Rogler, M.D., Ph.D.
Applicant Organization: University of Zürich (Switzerland)
Project Title: Snail blockage as a potential new approach to fistula therapy
Period of Award: October 1, 2009 – September 30, 2011

Intestinal fistulae are abnormal connections between the gut and other organs. They can occur between the bowel and the skin (entero-cutaneous fistulae), between different parts of the gut (entero-enteric fistulae) and between the gut and other organs such as the bladder (entero-vesical fistulae) or the vagina (entero-vaginal fistulae). Fistulae represent severe, sometimes disabling conditions, impairing the quality of life significantly.

Around 35% of all patients with Crohn’s disease (CD) suffer from fistulae at least once during their disease course. The therapeutic options for treating fistulae in CD are limited so far. Antibiotics, immunosuppressants and anti-TNF antibodies are established treatments; however, definitive fistula closure rates upon conservative treatment are around 30-40%. Therefore, fistulae are an important clinical problem. However, their pathophysiology is sparsely understood.

We recently found evidence that fistulae develop via a process called epithelial mesenchymal transition (EMT). This means that surface covering epithelial cells loose their contacts to their neighbouring cells and change their shape and behaviour. They become able to migrate rapidly and to invade the surrounding tissue. A trigger for this behavioural change could be a wound or ulcer those cells try to close. However, they do not stop to migrate into the tissue finally forming the fistula tracts described above.

Certain cellular factors have been identified that trigger EMT and that are necessary for the change of the shape and the behaviour of the epithelial cells. Among those factors are proteins of the so called SNAIL family as well as a protein called “Twist”.

As “Snail” and “Twist” are important factors for EMT and as this process plays an important role during fistula formation we hypothesize that blockade of these factors might stop fistula formation or induce fistula healing. Blockade of “Snail” or “Twist” could therefore be a new treatment option for CD patients suffering from fistulae.

In the proposed project we want to study the regulation of these factors during fistula formation and in tissue derived from fistula patients. We will investigate whether the blockade of “Snail” or “Twist” will reverse the changes that have taken place during EMT.