Lay Summary

Proposal No. IBD-0008
Principal Investigator:  Sander J. van Deventer, Ph.D., M.D.
Applicant Organization:  Academic Medical Centre Medical Research B.V. (Amsterdam, The Netherlands)
Project Title:  Treatment of Crohn's disease by Lactococcus lactis secreting human IL-10
Period of Award:  December 1, 2002 – November 30, 2003

The current challenge in developing new therapies for Crohn’s disease is to achieve long-standing remission.  Most therapies have the disadvantage of severe side effects when continuously administered.  Studies performed in animals have stressed the importance of interleukin-10 in maintaining tolerance towards autologous microflora in the gastro-intestinal system.  Interleukin-10 is a cytokine (compounds that regulate white cell activity).  These findings make interleukin-10 the most important novel therapeutic strategy in maintenance therapy of patients with Crohn’s disease.  Systemic treatment of interleukin-10 in patients with Crohn’s disease is not as effective as anti-TNF antibodies (antibodies to pro-inflammatory regulation of white cells) in reducing remission, but was shown to be safe and without adverse events.  Mouse interleukin-10 production by genetically modified Lactococcus lactis (a bacteria) was shown to be a highly efficient approach to the therapy of IBD in mice, indicating that mucosal delivery of interleukin-10 is crucial for its effect.

We have generated a Lactococcus lactis that is engineered to produce human interleukin-10.  We plan to administer these genetically engineered bacteria to IBD patients.  These bacteria will release human interleukin-10 at the mucosal surface at the site of inflammation.  The therapy has several advantages over more conventional treatments:  Lactococcus lactis is a non-pathogenic microorganism that can be easily eliminated by standard antibiotic therapy.  Moreover, it delivers interleukin-10 at the intestinal site where inflammation takes place, especially when the permeability, during periods of inflammation, is increased.  These experiments represent the first attempts to deliver biological drugs to the intestine surface by genetically engineered bacteria.  This new approach, if successful, will open up a new area of drug delivery to the intestinal surface by genetically engineered bacteria.