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Gene targeting by ribozyme against TNF-α mRNA inhibits autoimmune arthritis

Gene Therapy volume 12, pages 1486–1493 (2005)Cite this article

Abstract

Ribozymes are catalytic RNA that bind and cleave specific regions of target RNA. Therefore, protein synthesis by the target RNA may be specifically inhibited by ribozymes. In this study, we have investigated if ribozymes possess therapeutic activity on inflammatory processes in vivo, as judged from effects on an arthritis model. A hammerhead ribozyme against TNF-α was designed and its catalytic activity in vitro was verified. The ribozyme was employed in vivo without any delivery system, as the plasmid-based ribozyme was taken up adequately by various tissues in mice by intravenous injection. The ability of the ribozyme to regulate the development of collagen-induced arthritis (CIA), a model largely dependent on TNF-α, was investigated. Systemic administration of the ribozyme to mice immunized with collagen type II in CFA significantly reduced the development of CIA. No effect was observed with a catalytically inactive variant of the ribozyme. Furthermore, the ribozyme efficiently blocked cartilage and bone destruction in the joints and ameliorated established CIA. These data demonstrate for the first time that gene targeting by a ribozyme to inactivate TNF-α in vivo is highly efficient in suppressing autoimmune arthritis, thus providing proof of concept that it may be used as therapeutic tool for TNF-α-dependent chronic inflammatory disorders.

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Acknowledgements

We are thankful to Dr Angelio Corti for generously providing the pET mTNF-α construct and Professor Birgitta Heyman for critical reading and discussion. This work was supported by The Swedish Medical Research Council, The Swedish Rheumatism Association, The Swedish Psoriasis Association, The Swedish Society of Medicine, King Gustaf V's 80 Year Foundation, Åke Wiberg's Foundation, Magnus Bergvall's Foundation, The Professor Nanna Svartz Foundation and The Government of India (UGC, CSIR and DST).

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Authors and Affiliations

  1. Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

    R Kumar & S Kleinau

  2. Applied Molecular Biology Laboratory, School of Life Sciences, JNU, New Delhi, India

    R Kumar, V Dammai & P K Yadava

  3. Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden

    S Kleinau

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Kumar, R., Dammai, V., Yadava, P. et al. Gene targeting by ribozyme against TNF-α mRNA inhibits autoimmune arthritis. Gene Ther 12, 1486–1493 (2005). https://doi.org/10.1038/sj.gt.3302583

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