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[SANET-MG] Dutch courage



Crohn's disease is a chronic inflammatory disease of the intestines. It primarily causes ulcerations (breaks in the lining) of the small and large intestines, but can affect the digestive system anywhere from the mouth to the anus. It is named after the physician who described the disease in 1932. It also is called granulomatous enteritis or colitis, regional enteritis, ileitis, or terminal ileitis. Finding a cure for that disease is important as it effects around 1 person in a thousand in North America. Recently researchers in Holland treated ten people with a gut bacterium which had been modified with a synthetic approximation of a hum gene for the cytokine, interleukin 10. The test proved successful in relieving the symptoms of Crohn's disease. However, I found that the fate of the synthetic interleukin 10 gene in the microbial population was not well enough studied. The bacterium used in the experiment was modified so that it required thymidine to grow. The search for the actual fate of the synthetic interleukin genes was rather cursory and those permitting and overseeing the experiment seemed dangerously uncritical. The Dutch experiment is ,perhaps, the first to study humans using gene therapy delivery by microbes. The reason, perhaps, that the experimental controls were minimal was to promote many more experiments of that type on human subjects.The Dutch researchers were very brave.
Clin Gastroenterol Hepatol. 2006 May 19; [Epub ahead of print]

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

Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L.

Department of Experimental Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands.

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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