Induction of synovial apoptosis by gene transfer and peptide mediated protein transduction

The destruction of articular cartilage and bone due to pannus formation is one of the more clinically challenging problems associated with rheumatoid arthritis. While synovectomy, the physical removal or killing of synovial tissue, has demonstrated the ability to delay the degradation of the rheumatoid joint the various methods available for this procedure are either highly invasive or are associated with side effects. In order to combat these problems we have been developing a biological synovectomy technique based on the induction of apoptosis. Our approach has focused on the delivery of pro-apoptotic proteins to the diseased synovium either through gene transfer or direct peptide mediated protein delivery. Utilizing a rabbit model of RA we have examined the effects of over expressing a number of proapoptotic proteins (p53, FasL, TRAIL, granzymeB and activated caspase3) in the cells of the synovial lining. These experiments have demonstrated that the over expression of all of these proteins induce apoptosis in the synovial layer, albeit to differing extents. Intra-articular delivery of adenoviral vectors encoding the proapoptotic genes or proteins fused to peptide transduction domains results in extensive apoptosis in the cells of the synovial lining within 24 h after vector delivery. The induction of apoptosis in the synovium is also associated with a decrease in the inflammation observed in the treated joints. The magnitude of the reduction in leukocytic infiltration correlates directly with the extent of apoptosis induced. These data suggest that the over expression of proapoptotic proteins in synovium may have applications in the treatment of RA.