Gene silencing by systemic delivery of synthetic siRNAs in adult mice.
In mammalian cells, RNA duplexes of 21-23 nucleotides, known as small interfering RNAs (siRNAs) specifically inhibit gene expression in vitro. Here, we show that systemic delivery of siRNAs can inhibited exogenous and endogenous gene expression in adult mice. Cationic liposome-based intravenous injection in mice of plasmid encoding the green fluorescent protein (GFP) with its cognate siRNA, inhibited GFP gene expression in various organs. Furthermore, intraperitoneal injection of anti-TNF-alpha siRNA inhibited lipopolysaccharide-induced TNF-alpha gene expression, whereas secretion of IL1-alpha was not inhibited. Importantly, the development of sepsis in mice following a lethal dose of lipopolysaccharide injection, was significantly inhibited by pre-treatment of the animals with anti-TNF-alpha siRNAs. Collectively, these results demonstrate that synthetic siRNAs can function in vivo as pharmaceutical drugs.
Sørensen
Dag R
DR
Department of Comparative Medicine, The National Hospital, Oslo 0310, Norway.
Leirdal
Marianne
M
Sioud
Mouldy
M
D000818:Animals; D002412:Cations / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins; D008070:Lipopolysaccharides; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000378:metabolism; D034622:RNA Interference; D016372:RNA, Antisense / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000235:genetics* / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D002412:Cations; D008070:Lipopolysaccharides; D008081:Liposomes; D008164:Luminescent Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins