Gene therapy offers a new, radical approach to treatment for rheumatoid arthritis (RA). Our previous studies have demonstrated the therapeutic efficacy of antiinflammatory gene transfer in animal model of arthritis, and revealed the problems to be solved on the way to clinical trials. The most crucial issue concerns the selection of an appropriate target for intervention. As the inflammation is perpetuated by numerous autocrine/paracrine loops of cytokines and growth factors acting upon synovium, successful therapeutic approach should address the multiplicity of inflammatory pathways. Here we introduce a new strategy based on specific suppression of transcription factors. One transcriptional factor, NF-kappaB, appears to be a key mediator of inflammatory responses in arthritic synovium. Several lines of evidence suggest the pivotal role of NK-kappaB in the maintenance of inflammation: (1) Expression of majority of cytokines and growth factors found in inflamed synovium is transcriptionally controlled by NF-kappaB; (2) NF-kappaB is activated in inflamed synovium, and stimuli relevant to the pathogenesis of arthritis such as Il-1, TNFalpha, LPS, and bacterial products are potent inducers of NF-kappaB in synoviocytes in vitro; and (3) antiarthritic efficacy of glucocorticoids, NSAID's, and gold compounds correlates with their ability to suppress NF-kappaB. Thus the activation of NF-kappaB is synovium appears to be the point where the action of multiple inflammatory cytokines and growth factors converges. Therefore, we expect that suppression of NF-kappaB should downregulate the expression of cell adhesion molecules and inhibit the production of proinflammatory cytokines and growth factor. It is our hypothesis that inhibition of NF- kappaB in arthritic joints will provide effective treatment for the disease. Using specific inhibitors of NF-kappaB should spare the host from the multiple side effects associated with conventional drugs. To validate NF-kappaB as a target for gene therapy, we will attempt three distinctively different approaches for suppression of NF-kappaB-mediated transcription in synovium. The proposed approaches include delivery of antisense oligodeoxynucleotides, double-stranded 'decoy' DNA, and gene transfer of specific inhibitor of NF-kappaB, the IkappaB. Using inhibitors of NF-kappaB with different mechanisms of action should allow us to select the most effective treatment and provide clear-cut interpretation of the data. Inhibitory molecules to NF-kappaB will be initially tested in synoviocytes in vitro. Next, we will optimize intraarticular delivery of these inhibitors to synovium in vivo. Finally, immunomodulatory effects and the therapeutic efficacy will be examined in BCW arthritis in rats. Assessment of the feasibility of the new concept in an animal model of arthritis will facilitate development of clinically useful constructs.
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