Gene therapy for established murine collagen-induced arthritis by local and systemic adenovirus-mediated delivery of interleukin-4

RA is a chronic systemic autoimmune disease that is characterized by joint inflammation, and progressive cartilage and bone erosion. Currently the symptoms of arthritis are managed using pharmacologic agents, including both steroidal and nonsteroidal drugs, and disease-modifying drugs such as methotrexate. No pharmacologic agents have yet proven effective in halting the progression of disease, however. Recent research has identified certain biologic agents that appear more able than conventional therapies to halt effectively the progression of disease, as well as ameliorate disease symptoms. In particular, inhibitors of TNF-α and IL-1 have proven effective in clinical trials, and the US Food and Drug Administration has approved the use of soluble TNF-α receptor for treatment of human RA. One potential problem with the use of biologic agents for arthritis therapy is the need for daily or weekly repeat dosing. The transfer of genes directly to the synovial lining can theoretically circumvent the need for repeat dosing and reduce potential systemic side effects [ 1 , 2 ]. Ex-vivo and in-vivo methods have been used to deliver therapeutic genes such as those that encode IL-10, v-IL-10, soluble TNF and IL-1 receptors, and IL-1Ra to arthritic mouse [ 10 ], rat [ 11 ], dog [ 12 ], and rabbit joints [ 13 ]. Although many genes have been effective in treating murine CIA if they are administered before disease onset, local periarticular gene transfer has not been highly effective in halting the progression of established disease.