Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway.
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.
John
Matthias
M
Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany.
Constien
Rainer
R
Akinc
Akin
A
Goldberg
Michael
M
Moon
Young-Ah
YA
Spranger
Martina
M
Hadwiger
Philipp
P
Soutschek
Jürgen
J
Vornlocher
Hans-Peter
HP
Manoharan
Muthiah
M
Stoffel
Markus
M
Langer
Robert
R
Anderson
Daniel G
DG
Horton
Jay D
JD
Koteliansky
Victor
V
Bumcrot
David
D
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
D035683:MicroRNAs; D012333:RNA, Messenger