Vol.19 No.2

Original Article

Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets

Authors

Atsuo Inoue1,3 , Kenji A. Takahashi1 , Osam Mazda2 , Yuji Arai1 , Masazumi Saito1 , Tsunao Kishida2,4 , Masaharu Shin-Ya2 , Toru Morihara1 , Hitoshi Tonomura1 , Kei Sakao1 , Jiro Imanishi2 , Toshikazu Kubo1

  • Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
  • Department of Microbiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
  • Department of Orthopaedics, Kyoto First Red Cross Hospital, Kyoto 605-0981, Japan
  • Louis Pasteur Center for Medical Research, Kyoto 606-8225, Japan
Received:

10 June 2008

Accepted:

24 September 2008

Published online:

22 November 2008

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Abstract

RNA interference (RNAi) provides a powerful means of sequence-specific gene silencing. Several studies show that RNAi may provide promising strategies to treat human diseases by suppressing disease responsible genes in vivo. In locomotor diseases, the progression of collagen-induced arthritis (CIA) is suppressed by tumor necrosis factor-α (TNF-α)-specific small interfering RNA (siRNA) delivered into the joint. The aim of this study, is to compare the effects of intraarticularly administered siRNAs targeting TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6) and receptor activator of NF-κB ligand (RANKL) on CIA in rats. We confirmed that the silencing effects of siRNA duplexes specific for rat TNF-α, IL-1β, IL-6 and RANKL in vitro. Each siRNA was also delivered into the knee joint of CIA rats by the in vivo electroporation method 7, 10, 13 and 16 days after immunization with collagen. Local delivery of TNF-α or IL-1β-specific siRNA ameliorated CIA in rats effectively at the gross morphological, radiographical and histological evaluations. Our results suggested that TNF-α and IL-1β were the cytokines to be targeted in the joint for the treatment of rheumatoid arthritis. The in vivo siRNA transfection method may be useful for selection of target molecules to be silenced for treatment of joint diseases.

Key words

Collagen induced arthritis - Cytokines - Electroporation - Small interfering RNA