Original article
A Phase I Trial With Transgenic Bacteria Expressing Interleukin-10 in Crohn’s Disease

https://doi.org/10.1016/j.cgh.2006.03.028Get rights and content

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.

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Patient Selection and Treatment Regime

Patients were screened for eligibility 1 week before enrollment, once informed consent had been obtained. Eligible patients had Crohn’s disease, confirmed by routine endoscopic and histologic examination, for at least 3 months’ duration and a score on the CDAI ranging from 220–450. The CDAI incorporates 8 variables related to the disease activity: the number of liquid or very soft stools, the severity of abdominal pain or cramping, general well-being, the presence of extraintestinal

Study Design

The Medical Ethical Commission of the Academic Medical Center and the Dutch Administration of Public Health, Environment and Nature approved a limited clinical trail with LL-Thy12 in patients under physical containment (http://www.cogem.net). This study aimed at evaluating clinical as well as environmental safety of LL-Thy12. In total, 10 patients with moderate to severe Crohn’s disease (see Supplemental Table 1 at www.cghjournal.org) were included in the study. All patients were admitted to an

Discussion

We conducted the first human trial with a genetically engineered, therapeutic bacterium, and the results obtained indicate that such a strategy can be both safe for the patient as well as biologically contained. Such therapy encompasses important advances compared with current systemic treatment.

The clinical parameters obtained, including the assessment of adverse events and scoring for disease activity, showed that the topical application of recombinant proteins by L lactis–mediated delivery

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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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