Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist

Objective. To evaluate the recombinant adenoassociated virus vector encodin g interleukin-l receptor antagonist (rAAV-IL-1Ra) complementary DNA for its potential in the treatment and prevention of lipopolysaccharide (LPS)-indu ced arthritis. Methods. The therapeutic effect of rAAV-IL-1Ra on arthritis was studied by injecting knees of Sprague-Dawley rats with LPS and rAAV-IL-1Ra and then ev aluating the severity of arthritis by leukocyte counts in synovial fluid, h istologic changes of synovium, and uptake of Ga-67 citrate in joint tissue. To study the therapeutic effect on recurrent arthritis, we induced recurre nt arthritis by a second injection of LPS 80 days after primary LPS and rAA V-IL-1Ra injections and then evaluated the severity of recurrent arthritis. To study the prevention of arthritis, rAAV-IL-1Ra was injected into normal joints. After 100 days, LPS was used to induce arthritis, and the severity of arthritis was evaluated. Results. The production of the rAAV-IL-1Ra transgene was up-regulated by LP S-induced joint inflammation and proved to be efficacious in the therapeuti c and preventative protocols. Not only primary but also recurrent arthritis could be suppressed by a single injection of rAAV-IL-1Ra, We found that th e transgene expression of IL-1Ra could be reactivated by a second challenge with LPS delayed for 80 days after rAAV administration. The therapeutic le vel of IL-1Ra protein reached a mean +/- SD of 5.8 +/- 0.5 ng/ml in synovia l fluid. In addition, the rAAV transgene persisted within normal joints for at least 100 days and could still be induced to express, after LPS insult, a high level of IL-1Ra (mean +/- SD 5.2 +/- 0.8 ng/ml) that prevented the occurrence of arthritis. Conclusion. This gene therapy, by combining highly efficient and stable rAA V gene delivery, disease-regulated gene expression, and the antiinflammator y effect of IL-1Ra, provides a valuable approach for long-term protection a gainst, and prevention of, arthritis.