SUPPRESSION OF COLLAGEN-INDUCED ARTHRITIS THROUGH ADENOVIRUS-MEDIATEDTRANSFER OF A MODIFIED TUMOR-NECROSIS-FACTOR-ALPHA RECEPTOR GENE

Objective. To evaluate the efficacy of systemic and intraarticular ade noviral transfer of a modified tumor necrosis factor alpha receptor (T NF alpha R) gene and its expression in rat collagen-induced arthritis (CIA). Methods. Rats with CW received injections of replication-defici ent adenovirus containing either a TNF alpha inhibitor (TNFI) gene or a control beta-galactosidase (beta-gal) gene. The TNFI gene codes for a fusion protein consisting of the human 55-kd TNF alpha R and a mouse IgG heavy chain, Successful gene transfer was determined by serum TNF alpha R measurements and by histologic examination of injected joints with in situ blue staining. Results. Serum TNF alpha R levels were de tectable for 8 days following systemic TNFI gene transfer. CU severity was significantly suppressed by TNFI gene transfer, both prior to and following arthritis onset (P = 0.0001, by repeated-measures 2-factor analysis of variance), Direct synovial TNFI gene transfer was successf ul, but induced an inflammatory response without any net TNFI benefit. Conclusion. Systemic adenoviral-mediated transfer of the TNFI gene su ppressed CIA during its transitory expression, Intraarticular gene tra nsfer was limited by an adenoviral synovitis that was not overcome by delivery of the TNFI gene, TNFI is an excellent protein candidate for further therapeutic study.