title: Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50-70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5'-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.
authors.affiliation: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Frank-Kamenetsky
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.forename: Norma N
authors.initials: NN
authors.lastname: Anderson
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Racie
authors.forename: Birgit
authors.initials: B
authors.lastname: Bramlage
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: David
authors.initials: D
authors.lastname: Butler
authors.forename: Klaus
authors.initials: K
authors.lastname: Charisse
authors.forename: Robert
authors.initials: R
authors.lastname: Dorkin
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Fan
authors.forename: Christina
authors.initials: C
authors.lastname: Gamba-Vitalo
authors.forename: Philipp
authors.initials: P
authors.lastname: Hadwiger
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Matthias
authors.initials: M
authors.lastname: John
authors.forename: K Narayanannair
authors.initials: KN
authors.lastname: Jayaprakash
authors.forename: Martin
authors.initials: M
authors.lastname: Maier
authors.forename: Lubomir
authors.initials: L
authors.lastname: Nechev
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.forename: Timothy
authors.initials: T
authors.lastname: Read
authors.forename: Ingo
authors.initials: I
authors.lastname: Röhl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Soutschek
authors.forename: Pamela
authors.initials: P
authors.lastname: Tan
authors.forename: Jamie
authors.initials: J
authors.lastname: Wong
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Tracy
authors.initials: T
authors.lastname: Zimmermann
authors.forename: Antonin
authors.initials: A
authors.lastname: de Fougerolles
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Vornlocher
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood*; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D011323:Primates / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D008078:Cholesterol, LDL; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases