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Journal of Lipid Research, Vol. 48, 763-767, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Short Communication

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

Mark J. Graham¹, Kristina M. Lemonidis, Charles P. Whipple, Amuthakannan Subramaniam, Brett P. Monia, Stanley T. Crooke and Rosanne M. Crooke

Cardiovascular Group, Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92008

Published, JLR Papers in Press, January 22, 2007.

¹ To whom correspondence should be addressed. e-mail: mgraham{at}isisph.com

ABSTRACT

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 (ASO) inhibitors 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 by 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 reported previously 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 human.

Supplementary key words antisense oligonucleotides • low density lipoprotein receptor • hyperlipidemia

Abbreviations: apoB, apolipoprotein B; apobec1, apolipoprotein B mRNA editing enzyme catalytic polypeptide 1; ASO, antisense oligonucleotide; HF, high fat; LDLR, low density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SR-BI, scavenger receptor class B type I; TG, triglyceride

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