NUCLEASE-RESISTANT RIBOZYMES DECREASE STROMELYSIN MESSENGER-RNA LEVELS IN RABBIT SYNOVIUM FOLLOWING EXOGENOUS DELIVERY TO THE KNEE-JOINT

Catalytic RNA molecules, or ribozymes, have generated significant inte rest as potential therapeutic agents for controlling gene expression. Although ribozymes have been shown to work in vitro and in cellular as says, there are no reports that demonstrate the efficacy of synthetic, stabilized ribozymes delivered in vivo. We are currently utilizing th e rabbit model of interleukin 1-induced arthritis to assess the locali zation, stability, and efficacy of exogenous antistromelysin hammerhea d ribozymes, The matrix metalloproteinase stromelysin is believed to b e a key mediator in arthritic diseases, It seems likely therefore that inhibiting stromelysin would be a valid therapeutic approach for arth ritis. We found that following intraarticular administration ribozymes were taken up by cells in the synovial lining, were stable in the syn ovium, and reduced synovial interleukin 1 alpha-induced stromelysin mR NA, This effect was demonstrated with ribozymes containing various che mical modifications that impart nuclease resistance and that recognize several distinct sites on the message, Catalytically inactive ribozym es were ineffective, thus suggesting a cleavage-mediated mechanism of action, These results suggest that ribozymes may be useful in the trea tment of arthritic diseases characterized by dysregulation of metallop roteinase expression.