Feasibility of adenovirus-mediated nonsurgical synovectomy in collagen-induced arthritis-affected rhesus monkeys.
Gene transfer to synovial tissue by adenoviral vectors (Ad) was studied in vitro in cultured human synoviocytes and in vivo in seven primates with arthritis. Hyperplastic synovium was efficiently transduced with Ad.lacZ in vitro and in vivo in rhesus monkeys with collagen-induced arthritis, whereas chondrocytes were not transduced. Intraarticular injection of recombinant Ad harboring the luciferase gene showed the presence of reporter gene products only in Ad-injected joints. In addition, the feasibility of synovectomy by Ad harboring the herpes simplex virus thymidine kinase gene (tk) was studied. In vitro infection of synovium from rheumatoid arthritis patients with Ad.TK, followed by administration of ganciclovir, resulted in death of >90% of the synoviocytes. By mixing Ad.TK-infected with noninfected cells, it appeared that the presence of 10% infected synoviocytes resulted in the killing of more than 85% of the synoviocytes, demonstrating a substantial bystander effect. Intraarticular injection of Ad.TK in the knees of rhesus monkeys with arthritis, followed by treatment with ganciclovir for 14 days, resulted in increased apoptotic cell death in the synovium of Ad.TK-injected as compared with noninjected joints and ablation of the synovial lining layer. The procedure revealed no toxic side effects. These data suggest that nonsurgical synovectomy by tK gene therapy is feasible.
Goossens
P H
PH
Department of Rheumatology, Leiden University Medical Center, The Netherlands.
Schouten
G J
GJ
't Hart
B A
BA
Bout
A
A
Brok
H P
HP
Kluin
P M
PM
Breedveld
F C
FC
Valerio
D
D
Huizinga
T W
TW
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000628:therapy*; D003094:Collagen / Q000276:immunology; D015774:Ganciclovir / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000235:genetics*; D008253:Macaca mulatta; D018139:Simplexvirus / Q000201:enzymology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics
D000998:Antiviral Agents; D003094:Collagen; D008156:Luciferases; D013937:Thymidine Kinase; D015774:Ganciclovir