Nuclease-resistant ribozymes decrease stromelysin mRNA levels in rabbit synovium following exogenous delivery to the knee joint.
Catalytic RNA molecules, or ribozymes, have generated significant interest as potential therapeutic agents for controlling gene expression. Although ribozymes have been shown to work in vitro and in cellular assays, there are no reports that demonstrate the efficacy of synthetic, stabilized ribozymes delivered in vivo. We are currently utilizing the rabbit model of interleukin 1-induced arthritis to assess the localization, stability, and efficacy of exogenous antistromelysin hammerhead ribozymes. The matrix metalloproteinase stromelysin is believed to be a key mediator in arthritic diseases. It seems likely therefore that inhibiting stromelysin would be a valid therapeutic approach for arthritis. We found that following intraarticular administration ribozymes were taken up by cells in the synovial lining, were stable in the synovium, and reduced synovial interleukin 1 alpha-induced stromelysin mRNA. This effect was demonstrated with ribozymes containing various chemical modifications that impart nuclease resistance and that recognize several distinct sites on the message. Catalytically inactive ribozymes were ineffective, thus suggesting a cleavage-mediated mechanism of action. These results suggest that ribozymes may be useful in the treatment of arthritic diseases characterized by dysregulation of metalloproteinase expression.
Flory
C M
CM
Department of Immunopathology, Parke-Davis Pharmaceutical Research, Division Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Pavco
P A
PA
Jarvis
T C
TC
Lesch
M E
ME
Wincott
F E
FE
Beigelman
L
L
Hunt
S W
SW
Schrier
D J
DJ
D000818:Animals; D001168:Arthritis / Q000139:chemically induced* / Q000503:physiopathology; D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D017403:In Situ Hybridization; D007270:Injections, Intra-Articular; D007375:Interleukin-1 / Q000494:pharmacology; D007719:Knee Joint / Q000187:drug effects*; D008297:Male; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D016337:RNA, Catalytic / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D012260:Ribonucleases / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects*
D007375:Interleukin-1; D016337:RNA, Catalytic; D012333:RNA, Messenger; D012260:Ribonucleases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3