Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates

Maria Frank-Kamenetsky, Aldo Grefhorst, Norma N. Anderson, Timothy S. Racie, Birgit Bramlage, Akin Akinc, David Butler, Klaus Charisse, Robert Dorkin, Yupeng Fan, Christina Gamba-Vitalo, Philipp Hadwiger, Muthusamy Jayaraman, Matthias John, K. Narayanannair Jayaprakash, Martin Maier, Lubomir Nechev, Kallanthottathil G. Rajeev, Timothy Read, Ingo RöhlJürgen Soutschek, Pamela Tan, Jamie Wong, Gang Wang, Tracy Zimmermann, Antonin De Fougerolles, Hans Peter Vornlocher, Robert Langer, Daniel G. Anderson, Muthiah Manoharan, Victor Koteliansky, Jay D. Horton, Kevin Fitzgerald

Research output: Contribution to journalArticle

460 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11915-11920
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number33
DOIs
StatePublished - Aug 19 2008

Keywords

  • Plasma PCSK9
  • Tissue LDLR levels

ASJC Scopus subject areas

  • General

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    Frank-Kamenetsky, M., Grefhorst, A., Anderson, N. N., Racie, T. S., Bramlage, B., Akinc, A., Butler, D., Charisse, K., Dorkin, R., Fan, Y., Gamba-Vitalo, C., Hadwiger, P., Jayaraman, M., John, M., Jayaprakash, K. N., Maier, M., Nechev, L., Rajeev, K. G., Read, T., ... Fitzgerald, K. (2008). Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proceedings of the National Academy of Sciences of the United States of America, 105(33), 11915-11920. https://doi.org/10.1073/pnas.0805434105