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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
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
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
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