Treatment of murine collagen-induced arthritis by ex vivo extracellular superoxide dismutase gene transfer

Objective. Superoxide dismutase (SOD) is a potent antiinflammatory enzyme t hat has received growing attention for its therapeutic potential. This stud y was undertaken to examine the efficacy of extracellular SOD (EC-SOD) gene therapy in murine collagen-induced arthritis. Methods. Embryonic DBA/1 mouse fibroblasts were infected with a recombinant retrovirus expressing human EC-SOD. DBA/1 mice that had been treated with type II collagen were administered subcutaneous injections of 2 x 10(7) EC- SOD-expressing fibroblasts on day 29, when symptoms of arthritis were alrea dy present. The severity of arthritis in individual mice was evaluated in a double-blind manner, each paw was assigned a separate clinical score, and hind paw thickness was measured with a caliper. Mice were killed on day 50 for histologic examination of the joints. Results. High serum concentrations of EC-SOD were maintained for at least 7 days. Mice treated with the transgene exhibited significant suppression of clinical symptoms such as disabling joint swelling, deformity, and hind pa w thickness, compared with the untreated group (mean +/- SD maximum clinica l score in the untreated and the transgene-treated groups 2.71 +/- 1.08 and 1.35 +/- 1.22, respectively; P < 0.01, and hind paw thickness 3.04 +/- 0.1 8 nim and 2.56 +/- 0.12 mm, respectively; P < 0.05). Histologic abnormaliti es, including destruction of cartilage and bone, infiltration of mononuclea r cells, and proliferation of synovial cells, were also markedly improved i n the EC-SOD-treated mice compared with the control group (histopathologic score 7.50 +/- 1.13 and 4.13 +/- 1.88 in the untreated and transgene-treate d groups, respectively; P < 0.05). Conclusion. These results indicate that EC-SOD gene transfer may be an effe ctive form of therapy for rheumatoid arthritis.