Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA.

Abstract

Restoration of the impaired balance between pro-and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeutic proteins to arthritic joints. Here, we examined the efficacy of antiinflammatory gene therapy in bacterial cell wall-induced arthritis in rats. Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induced arthritis by using ex vivo gene transfer. To achieve this, primary synoviocytes were transduced in culture with a retroviral vector carrying the sIL-lra cDNA. Transduced cells were engrafted in ankle joints of animals prior to reactivation of arthritis. Animals in control groups were engrafted with synoviocytes transduced with lacZ and neo marker genes. Cells continued to express transferred genes for at least 9 days after engraftment. We found that gene transfer of sIL-lra significantly suppressed the severity of recurrence of arthritis, as assessed by measuring joint swelling and by the gross-observation score, and attenuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-lra was essentially local, as there was no significant difference in severity of recurrence between unengrafted contralateral joints in control and experimental groups. We estimate that locally expressed sIL-lra was about four orders of magnitude more therapeutically efficient than systemically administered recombinant sIL-lra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.

Gene therapy for arthritis

“…[33][34][35][36] The comparative degree to which they do this reflects the animal model being used. Thus, the effects of genes encoding IL-1 antagonists are marked and comprehensive in collagen-induced arthritis, whereas in antigen-induced arthritis there is a strong antierosive effect, but only a limited anti-inflammatory effect.…”

Anakinra, a recombinant human interleukin‐1 receptor antagonist (r‐metHuIL‐1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo‐controlled trial

“…Administration of IL-1Ra, either systemically or locally by gene transfer, reduces inflammation and joint damage in animal models of RA (20)(21)(22)(23). A recombinant form of human IL-1Ra, anakinra (recombinant methionyl human IL-1 receptor antagonist [r-metHuIL-1ra]), is a competitive antagonist of IL-1 that blocks the actions of IL-1 without any detectable agonist activity.…”

Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing

“…This strategy has not been as successful for primary OA treatment (29). IL-1Ra gene therapy, in which virus (30) or cells transduced ex vivo (31) are injected into the joint, has shown promise in animal models and has progressed to clinical trials, demonstrating the importance of IL-1 as a target in OA treatment and the potential of IL-1Ra as a therapeutic (reviewed in ref. 32).…”