Title:Therapeutic Effect of Ribbon-Type Nuclear Factor-κB Decoy Oligonucleotides in a Rat Model of Inflammatory Bowel Disease
Volume: 12
Issue: 6
Author(s): Kazunari Ozaki, Hirofumi Makino, Motokuni Aoki, Takashi Miyake, Natsuki Yasumasa, Mariana Kiomy Osako, Hironori Nakagami, Hiromi Rakugi and Ryuichi Morishita
Affiliation:
Keywords:
Inflammation, drug development, gene therapy, transcription factor, inflammation, drug development, gene therapy, transcription factor, S-ODNs, inflammatory bowel disease , dextran sulfate sodium (DSS)-induced colitis, disease activity index
Abstract: Background: The pathogenesis of inflammatory bowel disease (IBD) involves local expression of inflammatory
cytokines, some of which are coordinated by nuclear factor-κB (NF-κB). Several reports documented the therapeutic
potential of double-stranded phosphorothioated decoy oligonucleotides (S-ODNs) targeting NF-κB in IBD models. However,
S-ODNs are easily degraded by endonucleases. In this study, we employed newly developed nonchemically modified
ribbon-type NF-κB decoy ODNs (R-ODNs) with loop ends that increase the stability, and investigated their therapeutic
effect in rats with dextran sulfate sodium (DSS)-induced colitis.
Methodology/Principal Findings: We administered R-ODN, S-ODN, or scrambled ODN (Scr-ODN) to rats with DSSinduced
IBD using ultrasound with contrast microbubbles to enhance the transfection efficiency of ODN. Until day 10 after
DSS treatment, the rats showed a decrease in body weight and survival rate and an increase in the disease activity index
(DAI). In rats treated with S-ODN or R-ODN, the survival rate, colon length, and DAI were significantly improved.
In addition, DSS-induced expression of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β was significantly decreased.
Of importance, treatment with R-ODN was more effective to improve disease conditions as compared to S-ODN.
Conclusions: These data suggest that intracolonic administration of R-ODN may be effective to treat DSS-induced colitis.
