Lessons Learned From Gene Therapy Approaches

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Our ability to transfer genes to the synovial lining of joints allows the roles of various gene products in synovitis to be studied in novel ways. One strategy uses adenoviral vectors to transfer genes of interest to the synovial lining of normal and inflamed rabbits' knee joints. Rabbits are used because their knee joints are sufficiently large for reproducible intra-articular injection and lavage. Moreover, it is possible to study the responses of articular cartilage to disturbances occurring in the synovium. These studies need to be carefully performed as the adenoviral vector itself has inflammatory properties. Nevertheless, it is possible to gain important new information in this way.

When introduced into naive joints, vectors carrying IL-1β provoke a dramatic synovitis and pannus, which severely erode the adjacent cartilage. They also trigger systemic disturbances, including fever and weight loss. Oddly, the introduction of similar vectors carrying TNF produces only mild inflammatory and chondrodestructive changes. The TGF-β gene, in contrast, generates a massive fibrosis. The IGF-I and BMP-2 genes, on the other hand, produce few synovial changes and modestly elevate the synthesis of proteoglycans by cartilage.

When introduced into joints with antigen-induced arthritis, adenoviral vectors carrying genes encoding bivalent IL-1sR type I protect the articular cartilage and reduce the influx of leukocytes into the joint space. They do not, however, reduce synovitis or swelling. Similar vectors carrying bivalent TNFsR type I have no effect on cartilage and are only very weakly anti-inflammatory. Co-introduction of both vectors is strongly anti-inflammatory and chondroprotective. In animals with bivalent disease, there is also amelioration of disease in the contralateral knee joint that was not injected with the therapeutic genes. An even stronger effect on synovitis and associated joint pathologies was obtained with the viral IL-10 gene, which also produced a marked contralateral response. This effect has been reproduced in collagen-induced arthritis in mice.