Therapeutic effect of ribbon-type nuclear factor-κB decoy oligonucleotides in a rat model of inflammatory bowel disease.
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.


RESULTS
We administered R-ODN, S-ODN, or scrambled ODN (Scr-ODN) to rats with DSS-induced 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.
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan.
Kazunari
K
Ozaki
Hirofumi
H
Makino
Motokuni
M
Aoki
Takashi
T
Miyake
Natsuki
N
Yasumasa
Mariana Kiomy
MK
Osako
Hironori
H
Nakagami
Hiromi
H
Rakugi
Ryuichi
R
Morishita
D000818:Animals; D001835:Body Weight; D003106:Colon / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D009929:Organ Size; D051381:Rats; D012720:Severity of Illness Index; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014463:Ultrasonography
D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D016650:Fluorescein-5-isothiocyanate