We will explore the feasibility of suppressing inflammation by targeting intracellular transcription factors. The profile of inflammatory molecules suggests the pivotal role for NF-kB in the perpetuation of inflammation in arthritis. Thus activation of NF-kB in the synovium appears to be the point where the action of multiple inflammatory stimuli converges. It is our hypothesis that suppression of NF-kB in the synovium will provide a highly effective treatment for arthritis. We will test this hypothesis by using gene transfer of specific inhibitors of NF-kB. 2.
Infiltrating leukocytes are the major source of proinflammatory mediators in arthritis.
Gene transfer of inhibitory peptides will be attempted to block cell adherence and recruitment of leukocytes to inflamed joints. These peptides will be expressed as a multimeric pro-drug. Digestion of the prodrug by activated matrix proteinases will release active peptides providing inhibition of inflammation. Another proposed approach for the regulation of therapeutic transgene products is based on developing vectors allowing for the inflammation-regulated expression of the transgene. Another purpose of this study is to examine the impact of apoptosis in synovial cells on the duration of the transgene expression.