Interferon- Gene Therapy for the Treatment of Arthritis

Interferons were originally described as antiviral agents by Isaacs and Lindenmann (1 ). From its subtypes, fibroblast interferon (IFN-β) (2 ) was also found to have important cytostatic (3 ,4 ) as well as immunomodulatory functions (5) that have been advantageous for its clinical use both in cancer (6 ) and in autoimmune disease conditions such as multiple sclerosis (7 ,8 ) and, recently, in rheumatoid arthritis (9 ). As with many other cytokines, its local production is well controlled and environmental factors affect its expression. IFN-β has direct effects on the majority of cell types in the body, as its receptors are widely expressed in all tissues. Its use as a recombinant protein is limited because of its short half-life and production costs and its systemic delivery (subcutaneously) is inefficient, done at high doses and for long times using periodic administration. We and others have shown that the delivery of secreted biological compounds such as cytokines or their inhibitors (e.g., their soluble receptors) by gene therapy (10 -13 ) can in a single administration achieve long-term therapeutic effects at doses that are various logs of magnitude lower than those used with protein therapy. Gene therapy could also be designed to deliver the gene product locally, or its transcriptional control could be engineered so that is regulated using exogenously added drugs (14 ). IFN-β, as some other cytokines (e.g., interleukin [IL]-4, IFN-γ) is species-specific, and in order to obtain appropriate biological responses in mice, we had to clone the mouse gene by polymerase chain reaction (PCR).