title: Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.
abstract: 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.
authors.affiliation: Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany. jsoutschek@alnylam.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Soutschek
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: Birgit
authors.initials: B
authors.lastname: Bramlage
authors.forename: Klaus
authors.initials: K
authors.lastname: Charisse
authors.forename: Rainer
authors.initials: R
authors.lastname: Constien
authors.forename: Mary
authors.initials: M
authors.lastname: Donoghue
authors.forename: Sayda
authors.initials: S
authors.lastname: Elbashir
authors.forename: Anke
authors.initials: A
authors.lastname: Geick
authors.forename: Philipp
authors.initials: P
authors.lastname: Hadwiger
authors.forename: Jens
authors.initials: J
authors.lastname: Harborth
authors.forename: Matthias
authors.initials: M
authors.lastname: John
authors.forename: Venkitasamy
authors.initials: V
authors.lastname: Kesavan
authors.forename: Gary
authors.initials: G
authors.lastname: Lavine
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Pandey
authors.forename: Timothy
authors.initials: T
authors.lastname: Racie
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.forename: Ingo
authors.initials: I
authors.lastname: Röhl
authors.forename: Ivanka
authors.initials: I
authors.lastname: Toudjarska
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Silvio
authors.initials: S
authors.lastname: Wuschko
authors.forename: David
authors.initials: D
authors.lastname: Bumcrot
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Stefan
authors.initials: S
authors.lastname: Limmer
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Vornlocher
mesh_terms: 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
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002784:Cholesterol