Gene therapy targets for rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune inflammatory disease whose pathogenesis is not fully understood. The physiology of inflammation has been systematically studied and has provided specific targeted strategies for the modulation of inflammation. A number of biological agents targeted at reducing the inflammatory cascade of pathophysiological reactions have been developed. Some, such as interleukin-1 receptor antagonist (IL-1Ra), antitumour necrosis factor (TNF) α antibodies and TNF soluble receptors, have been tested and are now in use clinically. The clinical effects that have been observed are transient, necessitating repeated treatments. Advances in molecular biology have opened ways for the development of gene therapy in which specific genes are introduced, using either viral or non-viral ex vivo and in vivo gene transfer techniques, to locally enhance in vivo gene expression or suppress gene(s) of interest with a view to downregulating inflammatory responses. The proof of concept has been provided in a number of animal models of inflammatory arthritis. Strategies for production of cytokine inhibitors, such as soluble TNF receptors, or anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor β (TGF-β) and interferon β (IFN-β), have been developed. Other approaches involve the regulation of cartilage and bone erosion using IL-1Ra and tissue inhibitors of metalloproteinases, modulating apoptotic pathways in the rheumatoid synovium and the use of decoy oligonucleotides to nuclear factor κB (NF-κB), whose local application has been shown to be effective in downregulating joint inflammation in rat models of arthritis. Cytokines and other mediators play important physiological roles in the host’s defence system against infections and malignancy. Their chronic inhibition or their constitutive expression by gene therapy may lead to the development of side effects. Thus, carefully regulated gene expression during long-term studies will be required to assess the safety of selective targeting of processes involved in inflammation. This review summarises the important developments in gene therapy for RA.