J. Lipid Res.
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A more recent version of this article appeared on April 1, 2007

Papers In Press, published online ahead of print January 22, 2007
J. Lipid Res., doi:10.1194/jlr.C600025-JLR200
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Submitted on December 19, 2006
Revised on January 18, 2007
Accepted on January 21, 2007

Antisense inhibition of proprotein convertase subtilisin kexin 9 reduces serum LDL in hyperlipidemic mice

Mark J. Graham, Kristina M. Lemonidis, Charles P. Whipple, Amuthakannan Subramaniam, Brett P. Monia, Stanley T. Crooke, and Rosanne M. Crooke

Isis Pharmaceuticals, Carlsbad, CA 92008

Corresponding Author: mgraham{at}isisph.com

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of a family of proteases that is thought to promote the degradation of the low density lipoprotein receptor (LDLR) through an as yet undefined mechanism. We developed second generation antisense oligonucleotide inhibitors (ASOs) targeting murine PCSK9 to determine their potential as lipid lowering agents. Administration of a PCSK9 ASO to high fat fed mice for 6 weeks reduced total cholesterol and LDL, 53% and 38%, respectively. Moreover, inhibition of PCSK9 expression resulted in a 2-fold increase in hepatic LDLR protein levels. This phenotype closely resembles that previously reported in Pcsk9-deficient mice. The absence of cholesterol lowering in Ldlr-deficient mice effectively demonstrated a critical role for this receptor in mediating the lipid lowering effects of PCSK9 inhibition. Antisense inhibition of PCSK9 is an attractive and novel therapeutic approach for treating hypercholesterolemia in man.


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