Novel compounds for the treatment of inflammatory bowel disease
Inflammatory bowel diseases (IBD) such as Morbus Crohn or Colitis ulcerosa show increased local permeabilization of the gastrointestinal barrier, fuelling continuous infection and aggravated inflammation. IBD are characterized by persistent inflammatory reactions of the intestinal epithelium. The prevalence for both diseases is estimated at 250 per 100,000 in western industrialized countries and causes numerous events of sick-leaves and increasing economic pressure on health care systems.
As the etiology of IBD is not fully understood in general mainly the inflammatory symptoms are treated e. g. by immunomodulators such as infliximab, an anti-TNF alpha monoclonal antibody. This antibody has to be applied systemically to tackle local symptoms. This rationalises the huge amounts of antibodies necessary for the treatment, the tremendous and risky side effects as well as the enormous costs.
We focus on an alternative approach which does not employ an ´artificial´ pharmaceutical as the antibody but emphasizes the strengthening of an endogenous regulatory system like miRNAs, which are able to reinforce this barrier or even to restore the integrity of this barrier after disruption by enteropathogenic E. coli. This application might represent an attractive alternative for the current medication of IBD.
The present invention relates to the use of a nucleic acid molecule of up to 150 nucleotides, a fragment or variant thereof, which is capable to enhance the barrier function of the intestinal mucosa characterized by the transepithelial electrical resistance which is based on the integrity of the junctional complex. In particular the tight junctions represent a major barrier for paracellular transport, i.e.transport through the intercellular spaces between epithelial cells, and may prevent such passage of molecules and ions. The present invention also relates to a pharmaceutical composition comprising the nucleic acid and a fragment or variant thereof which is coupled to a transport system.
This composition is capable to mimic the positive effects of probiotics such as E.coli Nissle 1917 on intestinal epithelial cells which is at least as successfully as a common drug treatment (i.e. with mesalazine). Furthermore the invention is supposed to have a positive effect on the decrease in the translocation of microorganisms across the intestinal epithelium (stabilization of barrier function), on the modulation of immunological processes, the maintenance of the ecological balance in the gut and on the reduction of colonization with pathogenic bacteria.
New aspects and advantages of the invention
A single, short nucleic acid is capable to simulate the beneficial effect of restoring the barrier function of intestinal epithelial cells by probiotic bacteria.
Particular important aspects include
- in vitro model for IBD (T84) cells reveals barrier function enhancing effect
- positive impact on the transepithelial resistance (TER) of epithelial cells
- prevent the barrier disruptive effect of enteropathogenic E.coli (EPEC) or restore barrier integrity
- preventing the permeabilization of the gastrointestinal barrier and thereby the translocation of bacteria and the induction of an inflammatory processes
- therapy for IBD which is comparable to probiotics or Mesalazine (without side effects)
The described nucleic acid has a main function useful for therapeutic applications:
- it can be applied to tackle IBD in a way comparable to probiotic bacteria
and in addition potential diagnostic advantages:
- preliminary data for two in vivo colitis mouse models indicate the correlation of specific RNA expression with histological phenomena of IBD
- therefore the particular RNA might be used to characterise the inflammatory status of the gut.
A European and PCT patent application have been filed.