A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease.
Clin Gastroenterol Hepatol
; 4(6): 754-9, 2006 Jun.
Article
em En
| MEDLINE
| ID: mdl-16716759
ABSTRACT
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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Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Doença de Crohn
/
Interleucina-10
/
Lactococcus lactis
Tipo de estudo:
Clinical_trials
Limite:
Humans
Idioma:
En
Revista:
Clin Gastroenterol Hepatol
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Holanda