A Phase I Trial With Transgenic Bacteria Expressing Interleukin-10 in Crohn's Disease

Henri Braat, Pieter Rottiers, Daniel W. Hommes, Nathalie Huyghebaert, Erik Remaut, Jean Paul Remon, Sander J.H. van Deventer, Sabine Neirynck, Maikel P. Peppelenbosch*, Lothar Steidler

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

608 Citations (Scopus)


Background & Aims: The use of living, genetically modified bacteria is an effective approach for topical delivery of immunomodulatory proteins. This strategy circumvents systemic side effects and allows long-term treatment of chronic diseases. However, treatment of patients with a living, genetically modified bacterium raises questions about the safety for human subjects per se and the biologic containment of the transgene. Methods: We treated Crohn's disease patients with genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene was replaced with a synthetic sequence encoding mature human interleukin-10. Ten patients were included in a placebo-uncontrolled trial. Patients were assessed daily for the presence of potential adverse effects by direct questioning and assessment of disease activity. We evaluated the presence and kinetics of LL-Thy12 release in the stool of patients by conventional culturing and quantitative polymerase chain reaction of LL-Thy12 gene sequences. Results: Treatment with LL-Thy12 was safe because only minor adverse events were present, and a decrease in disease activity was observed. Moreover, fecally recovered LL-Thy12 bacteria were dependent on thymidine for growth and interleukin-10 production, indicating that the containment strategy was effective. Conclusions: Here we show that the use of genetically modified bacteria for mucosal delivery of proteins is a feasible strategy in human beings. This novel strategy avoids systemic side effects and is biologically contained; therefore it is suitable as maintenance treatment for chronic intestinal disease.

Original languageEnglish
Pages (from-to)754-759
Number of pages6
JournalClinical Gastroenterology and Hepatology
Issue number6
Publication statusPublished - Jun 2006
Externally publishedYes

Bibliographical note

Funding Information:
H.B. was supported by the Broad Medical Research Program. D.W.H. is Clinical Fellow of The Netherlands Organization for Health Research and Development. The Science Foundation Ireland (SFI/01/F.1/B036) partly supported L.S. and S.N. M.P. is supported by the “Maag Lever Darm Stichting.” P.R is supported by the Flanders Interuniversity Institute for Biotechnology. E.R., N.H., and J.P.R. are supported by the Research Fund of Ghent University (GOA project no. 12050700).


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