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

[ Vol. 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   Pages 484 - 492 ( 9 )

Abstract:


Background: The pathogenesis of inflammatory bowel disease (IBD) involves local expression of inflammatory cytokines, some of which are coordinated by nuclear factor-κ B (NF-κ B). 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

Affiliation:

Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.



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