Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates
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- Maria Frank-Kamenetsky
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Aldo Grefhorst
- Departments of †Molecular Genetics and
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- Norma N. Anderson
- Departments of †Molecular Genetics and
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- Timothy S. Racie
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Birgit Bramlage
- Roche Kulmbach GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany; and
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- Akin Akinc
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- David Butler
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Klaus Charisse
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Robert Dorkin
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Yupeng Fan
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Christina Gamba-Vitalo
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Philipp Hadwiger
- Roche Kulmbach GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany; and
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- Muthusamy Jayaraman
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Matthias John
- Roche Kulmbach GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany; and
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- K. Narayanannair Jayaprakash
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Martin Maier
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Lubomir Nechev
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Kallanthottathil G. Rajeev
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Timothy Read
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Ingo Röhl
- Roche Kulmbach GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany; and
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- Jürgen Soutschek
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Pamela Tan
- Roche Kulmbach GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany; and
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- Jamie Wong
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Gang Wang
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Tracy Zimmermann
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Antonin de Fougerolles
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Hans-Peter Vornlocher
- Roche Kulmbach GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany; and
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- Robert Langer
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139
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- Daniel G. Anderson
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139
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- Muthiah Manoharan
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Victor Koteliansky
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
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- Jay D. Horton
- Departments of †Molecular Genetics and
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- Kevin Fitzgerald
- *Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142;
説明
<jats:p> 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 <jats:italic>in vivo</jats:italic> 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. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 105 (33), 11915-11920, 2008-08-19
Proceedings of the National Academy of Sciences
