A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease

Clin Gastroenterol Hepatol. 2006 Jun;4(6):754-9. doi: 10.1016/j.cgh.2006.03.028. Epub 2006 May 22.


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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • C-Reactive Protein / analysis
  • Crohn Disease / pathology
  • Crohn Disease / therapy*
  • Genetic Therapy*
  • Humans
  • Interleukin-10 / administration & dosage*
  • Interleukin-10 / genetics
  • Lactococcus lactis* / genetics
  • Lactococcus lactis* / metabolism
  • Organisms, Genetically Modified
  • Tablets, Enteric-Coated
  • Thymidylate Synthase / genetics
  • Transgenes


  • Tablets, Enteric-Coated
  • Interleukin-10
  • C-Reactive Protein
  • Thymidylate Synthase