title: Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway.
abstract: Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (approximately 80%) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.
authors: Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany.
authors: Matthias
authors: M
authors: John
authors: Rainer
authors: R
authors: Constien
authors: Akin
authors: A
authors: Akinc
authors: Michael
authors: M
authors: Goldberg
authors: Young-Ah
authors: YA
authors: Moon
authors: Martina
authors: M
authors: Spranger
authors: Philipp
authors: P
authors: Hadwiger
authors: Jürgen
authors: J
authors: Soutschek
authors: Hans-Peter
authors: HP
authors: Vornlocher
authors: Muthiah
authors: M
authors: Manoharan
authors: Markus
authors: M
authors: Stoffel
authors: Robert
authors: R
authors: Langer
authors: Daniel G
authors: DG
authors: Anderson
authors: Jay D
authors: JD
authors: Horton
authors: Victor
authors: V
authors: Koteliansky
authors: David
authors: D
authors: Bumcrot
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D006224:Cricetinae; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger