Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PC) family of subtilisin-like serine endoproteases that regulates low density lipoprotein receptor (LDLR) levels and function. Loss of PCSK9 protein (in murine models, as well as, in human individuals) increases LDLR levels while excess PCSK9 decreases LDLR levels. These changes in LDLR protein levels coincide with reciprocal changes in circulating levels of plasma LDL cholesterol. Angiopoietin-like 3 (ANGPTL3) is a member of the angiopoietin-like family of secreted proteins. Similar to PCSK9, it is predominantly expressed in the liver. ANGPTL3 acts as dual inhibitor of both lipoprotein and endothelial lipases. Animal studies as well as human genetic studies suggest that siRNA silencing of PCSK9 should result in substantial decrease in LDLc. Similar studies have suggested that liver silencing of ANGPTL3 should result in profound lowering of LDLc, Triglycerides and HDLc, while maintaining the HDLc/LDLc ratio. We have developed highly potent RNAi therapeutics targeting both PCSK9 and ANGPTL3. Pre-clinical data utilizing intravenous infusion of siRNA formulated in lipid nanoparticles, and subcutaneous delivery of siRNA-GalNAc conjugates will be discussed.
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