Mucosal gene therapy using a pseudotyped lentivirus vector encoding murine interleukin-10 (mIL-10) suppresses the development and relapse of experimental murine colitis
1 Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at the University of California (UCLA), Los Angeles, CA, USA
2 Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at the University of California (UCLA), Los Angeles, CA, USA
3 Magee-Womens Research Institute, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4 Division of Gastroenterology and Ultrasonography and Translational Medical Science and Nutrition (GUT), Kawasaki Medical School, Okayama, Japan
5 Division of Gastroenterology, East Hospital of National Cancer Institute, Chiba, Japan
6 Division of Thoracic Surgery, Hokkaido University, Hokkaido, Japan
7 Division of Urology, Jikei University School of Medicine, Tokyo, Japan
BMC Gastroenterology 2014, 14:68 doi:10.1186/1471-230X-14-68Published: 8 April 2014
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.
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.
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.
Topically-delivered lentiviral vectors encoding interleukin-10 safely penetrated local mucosal tissue and had therapeutic benefit in this DSS model of murine colitis.