Therapeutic Effect of Ribbon-Type Nuclear Factor-κB Decoy Oligonucleotides in a Rat Model of Inflammatory Bowel Disease

Kazunari      Ozaki; Hirofumi      Makino; Motokuni      Aoki; Takashi      Miyake; Natsuki      Yasumasa; Mariana      Kiomy Osako; Hironori      Nakagami; Hiromi      Rakugi; Ryuichi      Morishita

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.

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