Mucosal gene therapy using a pseudotyped lentivirus vector encoding murine interleukin-10 (mIL-10) suppresses the development and relapse of experimental murine colitis.
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.
Hiroshi
H
Matsumoto
Kazunori
K
Haga
Izumi
I
Ohno
Kei
K
Hiraoka
Takahiro
T
Kimura
Kip
K
Hermann
Noriyuki
N
Kasahara
Peter
P
Anton
Magee-Womens Research Institute, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. imcgowan@pitt.edu.
Ian
I
McGowan
D058956:Administration, Mucosal; D000285:Administration, Rectal; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control / Q000628:therapy*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016753:Interleukin-10 / Q000235:genetics*; D016086:Lentivirus; D051379:Mice; D008807:Mice, Inbred BALB C; D012008:Recurrence
C556062:IL10 protein, mouse; D016753:Interleukin-10; D016264:Dextran Sulfate