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

Abstract

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 × 107 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.

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

“…We found that mitochondrial alterations are significantly reduced in the presence of SOD and NAC, coupled with a reduction in mitochondrial genome mutagenesis, a decrease in oxidative stress levels, and altered mitochondrial membrane potential. Previous studies using mouse models of arthritis showed reduced levels of proinflammatory cytokines after treatment with SOD (43). Furthermore, the finding of increased numbers of blood vessels in SOD-1 Ϫ/Ϫ mice (44) suggests that ROS play a role in regulation of angiogenesis.…”

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

“…-associated oxidative stress by enhancing ecSOD has been applied successfully in various experimental disease models [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] (Table I). For example, ecSOD has been shown to restore erectile function in streptozotocin-induced diabetes, 33 protect against vascular dysfunction with aging, 19 blunt ischemia/reperfusion-induced liver injury, 32 reduce systemic vascular resistance and arterial pressure in spontaneously hypertensive rats, 21 improve endothelial dysfunction in hypertension and in heart failure models, 23,35 and ameliorate inflammatory arthritis.…”

“…For example, ecSOD has been shown to restore erectile function in streptozotocin-induced diabetes, 33 protect against vascular dysfunction with aging, 19 blunt ischemia/reperfusion-induced liver injury, 32 reduce systemic vascular resistance and arterial pressure in spontaneously hypertensive rats, 21 improve endothelial dysfunction in hypertension and in heart failure models, 23,35 and ameliorate inflammatory arthritis. 28,29 In most of the aforementioned studies, human ecSOD gene transfer was employed to augment ecSOD activity in animal models. Regarding the behavior and fate of the delivered foreign gene in recipient hosts, most studies showed an increase of ecSOD activity, with a corresponding decrease in levels, after gene transfer (Table I).…”

Gene therapy for arthritis

“…83 To affect cytokine, adhesion molecules and MMP gene expression small dsDNA oligonucleotides containing the NF-kB binding site were used to serve as decoys and compete for binding of NF-kB at the transcriptional level. 84,43,45 Therapeutic interventions to ameliorate the formation of free radicals, which mediate part cartilage and bone destruction via oxidative stress, include expression of extracellular superoxide dismutase (EC-SOD) from syngeneic fibroblasts 85 injected s.c. or in combination with catalase from immortalized syngeneic synoviocytes injected i.a. or s.c. 86 To inhibit matrix metalloproteinase (MMP) activity, TIMP-1 was expressed from an adenovirus vector injected i.v.…”