Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.
RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.
Soutschek
Jürgen
J
Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany. jsoutschek@alnylam.de
Akinc
Akin
A
Bramlage
Birgit
B
Charisse
Klaus
K
Constien
Rainer
R
Donoghue
Mary
M
Elbashir
Sayda
S
Geick
Anke
A
Hadwiger
Philipp
P
Harborth
Jens
J
John
Matthias
M
Kesavan
Venkitasamy
V
Lavine
Gary
G
Pandey
Rajendra K
RK
Racie
Timothy
T
Rajeev
Kallanthottathil G
KG
Röhl
Ingo
I
Toudjarska
Ivanka
I
Wang
Gang
G
Wuschko
Silvio
S
Bumcrot
David
D
Koteliansky
Victor
V
Limmer
Stefan
S
Manoharan
Muthiah
M
Vornlocher
Hans-Peter
HP
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007275:Injections, Intravenous; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D034622:RNA Interference / Q000187:drug effects*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D012680:Sensitivity and Specificity
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002784:Cholesterol