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.
Highlights
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
As observed previously in Pcsk9deficient mice [3], suppression of PCSK9 did not affect the levels of hepatic LDLR or apolipoprotein B (apoB) mRNA
We demonstrate for the first time that administration of a second generation PCSK9 antisense oligonucleotide (ASO) to hyperlipidemic mice reduced hepatic PCSK9 mRNA expression by 92% and resulted in significant reductions in total cholesterol and LDL
Summary
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. 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. To determine whether pharmacological inhibition of PCSK9 decreases LDL through upregulation of LDLR protein, an antisense oligonucleotide (ASO) complementary to the mouse PCSK9 gene was identified and administered to hyperlipidemic mice. Lipid lowering was dependent on a functional LDLR These findings validate PCSK9 as a pharmacological target for LDL lowering and suggest that the specific and selective inhibition of PCSK9 mRNA using ASOs may be an effective approach for decreasing LDL in human. Mechanistic studies in Pcsk9-deficient mice have shown that inactivation of this gene produces ?2-fold increases in hepatic low density lipoprotein receptors (LDLRs), resulting in significant reductions in LDL via an enhanced hepatic clearance mechanism [4].
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