Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor ?B decoy oligodeoxynucleotides as a gene therapy

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Abstract
Objective In both rheumatoid arthritis and collagen‐induced arthritis (CIA), the nuclear factor κB (NF‐κB) transcription factor plays a pivotal role in the coordinated transactivation of many cytokines related to pathogenesis. This study investigated whether synthetic double‐stranded DNA that show a high affinity for NF‐κB could be introduced in vivo as “decoy” cis elements to bind the transcription factor and block the activation of such proinflammatory cytokine genes as interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα), and thus suppress the severity of joint destruction. Methods NF‐κB decoy oligonucleotides (ODN) were introduced by an intraarticular injection into the bilateral hind ankle joints of CIA rats using the hemagglutinating virus of Japan (HVJ)–liposome method. Joint destruction was evaluated by histology and radiography. IL‐1 and TNFα levels were assessed by enzyme‐linked immunosorbent assay and Northern blot analysis. Results Using the HVJ‐liposome method, the presence of fluorescein isothiocyanate–labeled ODN in the synovium was confirmed until 28 days after intraarticular injection. In vivo transfection of NF‐κB decoy ODN by an intraarticular injection into CIA rats decreased the severity of hind‐paw swelling. Histologic and radiographic studies showed a marked suppression of joint destruction treated by NF‐κB decoy ODN transfection. This treatment method also suppressed the production of IL‐1 and TNFα in the synovium of arthritic joints. Conclusion The present results demonstrate that administration of NF‐κB decoy ODN in arthritic joints of rats with CIA led to an amelioration of arthritis. These findings suggest that intraarticular transfection of NF‐κB decoy ODN may provide a useful therapeutic approach for the treatment of inflammatory arthritis.