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

Objective Superoxide dismutase (SOD) is a potent antiinflammatory enzyme that has received growing attention for its therapeutic potential. This study 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 × 10 7 EC‐SOD–expressing fibroblasts on day 29, when symptoms of arthritis were already 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 paw thickness, compared with the untreated group (mean ± SD maximum clinical 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 ± 0.18 mm and 2.56 ± 0.12 mm, respectively; P < 0.05). Histologic abnormalities, including destruction of cartilage and bone, infiltration of mononuclear cells, and proliferation of synovial cells, were also markedly improved in 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‐treated groups, respectively; P < 0.05). Conclusion These results indicate that EC‐SOD gene transfer may be an effective form of therapy for rheumatoid arthritis.