TY - JOUR
T1 - Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates
AU - Frank-Kamenetsky, Maria
AU - Grefhorst, Aldo
AU - Anderson, Norma N.
AU - Racie, Timothy S.
AU - Bramlage, Birgit
AU - Akinc, Akin
AU - Butler, David
AU - Charisse, Klaus
AU - Dorkin, Robert
AU - Fan, Yupeng
AU - Gamba-Vitalo, Christina
AU - Hadwiger, Philipp
AU - Jayaraman, Muthusamy
AU - John, Matthias
AU - Jayaprakash, K. Narayanannair
AU - Maier, Martin
AU - Nechev, Lubomir
AU - Rajeev, Kallanthottathil G.
AU - Read, Timothy
AU - Röhl, Ingo
AU - Soutschek, Jürgen
AU - Tan, Pamela
AU - Wong, Jamie
AU - Wang, Gang
AU - Zimmermann, Tracy
AU - De Fougerolles, Antonin
AU - Vornlocher, Hans Peter
AU - Langer, Robert
AU - Anderson, Daniel G.
AU - Manoharan, Muthiah
AU - Koteliansky, Victor
AU - Horton, Jay D.
AU - Fitzgerald, Kevin
PY - 2008/8/19
Y1 - 2008/8/19
N2 - 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.
AB - 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.
KW - Plasma PCSK9
KW - Tissue LDLR levels
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U2 - 10.1073/pnas.0805434105
DO - 10.1073/pnas.0805434105
M3 - Article
C2 - 18695239
AN - SCOPUS:50149101511
SN - 0027-8424
VL - 105
SP - 11915
EP - 11920
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -