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01.12.2014 | Research article | Ausgabe 1/2014 Open Access

BMC Gastroenterology 1/2014

Mucosal gene therapy using a pseudotyped lentivirus vector encoding murine interleukin-10 (mIL-10) suppresses the development and relapse of experimental murine colitis

Zeitschrift:
BMC Gastroenterology > Ausgabe 1/2014
Autoren:
Hiroshi Matsumoto, Kazunori Haga, Izumi Ohno, Kei Hiraoka, Takahiro Kimura, Kip Hermann, Noriyuki Kasahara, Peter Anton, Ian McGowan
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1471-230X-14-68) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interest.

Authors’ contributions

HM conducted the majority of the experiments described in this paper. TK carried out the molecular genetic studies, made the lentiviral vector, and performed the statistical analysis of the experimental data. KH, IO, KH helped to analyze the in vivo animal data. NK provided technical assistance for the lentiviral vector experiments, PA collected the endoscopic biopsies, and IM supervised the research, and edited the final manuscript. All authors read and approved the final manuscript.

Abstract

Background

Therapeutic gene transfer is currently being evaluated as a potential therapy for inflammatory bowel disease. This study investigates the safety and therapeutic benefit of a locally administered lentiviral vector encoding murine interleukin-10 in altering the onset and relapse of dextran sodium sulfate induced murine colitis.

Methods

Lentiviral vectors encoding the reporter genes firefly-luciferase and murine interleukin-10 were administered by intrarectal instillation, either once or twice following an ethanol enema to facilitate mucosal uptake, on Days 3 and 20 in Balb/c mice with acute and relapsing colitis induced with dextran sulfate sodium (DSS). DSS colitis was characterized using clinical disease activity, macroscopic, and microscopic scores. Bioluminescence optical imaging analysis was employed to examine mucosal lentiviral vector uptake and transgene expression. Levels of tumor necrosis factor-α and interleukin-6 in homogenates of rectal tissue were measured by ELISA. Biodistribution of the lentiviral vector to other organs was evaluated by real time quantitative PCR.

Results

Mucosal delivery of lentiviral vector resulted in significant transduction of colorectal mucosa, as shown by bioluminescence imaging analysis. Lentiviral vector-mediated local expression of interleukin-10 resulted in significantly increased levels of this cytokine, as well as reduced levels of tumor necrosis factor-α and interleukin-6, and significantly reduced the clinical disease activity, macroscopic, and microscopic scores of DSS colitis. Systemic biodistribution of locally instilled lentiviral vector to other organs was not detected.

Conclusions

Topically-delivered lentiviral vectors encoding interleukin-10 safely penetrated local mucosal tissue and had therapeutic benefit in this DSS model of murine colitis.
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