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 x 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).


CONCLUSIONS
These results indicate that EC-SOD gene transfer may be an effective form of therapy for rheumatoid arthritis.
Iyama
S
S
Sapporo Medical University School of Medicine, Japan.
Okamoto
T
T
Sato
T
T
Yamauchi
N
N
Sato
Y
Y
Sasaki
K
K
Takahashi
M
M
Tanaka
M
M
Adachi
T
T
Kogawa
K
K
Kato
J
J
Sakamaki
S
S
Niitsu
Y
Y
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D003470:Culture Media; D005110:Extracellular Space / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D007596:Joints / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D013482:Superoxide Dismutase / Q000097:blood / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D003470:Culture Media; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D013482:Superoxide Dismutase