Gene targeting by ribozyme against TNF-alpha mRNA inhibits autoimmune arthritis.
Ribozymes are catalytic RNA that bind and cleave specific regions of target RNA. Therefore, protein synthesis by the target RNA may be specifically inhibited by ribozymes. In this study, we have investigated if ribozymes possess therapeutic activity on inflammatory processes in vivo, as judged from effects on an arthritis model. A hammerhead ribozyme against TNF-alpha was designed and its catalytic activity in vitro was verified. The ribozyme was employed in vivo without any delivery system, as the plasmid-based ribozyme was taken up adequately by various tissues in mice by intravenous injection. The ability of the ribozyme to regulate the development of collagen-induced arthritis (CIA), a model largely dependent on TNF-alpha, was investigated. Systemic administration of the ribozyme to mice immunized with collagen type II in CFA significantly reduced the development of CIA. No effect was observed with a catalytically inactive variant of the ribozyme. Furthermore, the ribozyme efficiently blocked cartilage and bone destruction in the joints and ameliorated established CIA. These data demonstrate for the first time that gene targeting by a ribozyme to inactivate TNF-alpha in vivo is highly efficient in suppressing autoimmune arthritis, thus providing proof of concept that it may be used as therapeutic tool for TNF-alpha-dependent chronic inflammatory disorders.
Kumar
R
R
Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Dammai
V
V
Yadava
P K
PK
Kleinau
S
S
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D005260:Female; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D007074:Immunoglobulin G / Q000276:immunology; D007269:Injections, Intra-Arterial; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016337:RNA, Catalytic / Q000008:administration & dosage*; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D007074:Immunoglobulin G; D016337:RNA, Catalytic; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha