INTRAARTICULAR EXPRESSION OF BIOLOGICALLY-ACTIVE INTERLEUKIN-1 RECEPTOR-ANTAGONIST PROTEIN BY EX-VIVO GENE-TRANSFER

Gene therapy offers a radical different approach to the treatment of a rthritis. Here we have demonstrated that two marker genes (lacZ and ne o) and cDNA coding for a potentially therapeutic protein (human interl eukin 1-receptor-antagonist protein; IRAP or IL-1ra) can be delivered, by ex vivo techniques, to the synovial lining of joints; intraarticul ar expression of IRAP inhibited intraarticular responses to interleuki n 1. To achieve this, lapine synoviocytes were first transduced in cul ture by retroviral infection. The genetically modified synovial cells were then transplanted by intraarticular injection into the knee joint s of rabbits, where they efficiently colonized the synovium. Assay of joint lavages confirmed the in vivo expression of biologically active human IRAP. With allografted cells, IRAP expression was lost by 12 day s after transfer. In contrast, autografted synoviocytes continued to e xpress IRAP for almost-equal-to 5 weeks. Knee joints expressing human IRAP were protected from the leukocytosis that otherwise follows the i ntraarticular injection of recombinant human interleukin 1beta. Thus, we report the intraarticular expression and activity of a potentially therapeutic protein by gene-transfer technology; these experiments dem onstrate the feasibility of treating arthritis and other joint disorde rs with gene therapy.