With the recent studies on PCSK9, it is now increasingly clear that PCSK9 has pro-atherosclerotic effects and regulates lipoprotein synthesis. Meanwhile, several studies have indicated the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia). At Creative Biolabs who is focused on animal model and antibody drug discovery, the humanized PCSK9 immune checkpoint knock-in mice are now available with professional technical support.

PCSK9 Molecule

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the 9th member of the proprotein convertase family of proteins that activate other proteins. PCSK9 is a central regulatory molecule that inhibits clearance of endogenous cholesterol lipid from the blood and is ubiquitously expressed in many tissues and cell types. PCSK9 is a typical PCSK because it has a serine esterase - like the structure of the bacterial subtilase family but differs due to the similarity with proteinase K.

The Mechanism and Function of PCSK9 Signaling

PCSK9 binds the LDL (low-density lipoprotein) receptor on the surface of liver cells. The LDL receptor (LDLR) binds and initiates ingestion of LDL-particles from extracellular fluid into cells, thus reducing LDL particle concentrations. When bound to PSCK9, the LDL receptor is degraded and is no longer recycled back to the cell membrane surface to bind and ingest more LDL-particles after the LDL-LDLR particle combination has been ingested, thus resulting in reduced removal of LDL cholesterol from the blood. By blocking PCSK9, more LDLRs are recycled and are present on the surface of cells to clear LDL cholesterol from the extracellular fluid such as blood, resulting in reducing LDL cholesterol levels. Similar to many other proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.

The Clinical Significance of PCSK9

According to the latest research, PCSK9 inhibition could ameliorate atherosclerosis and thus cardiovascular disease by immune mechanisms that are unrelated to lowering of low-density lipoprotein (LDL) cholesterol. It has been shown that T cells and dendritic cells are common in atherosclerotic plaques. And atherosclerosis is a chronic inflammatory process in which activation of these immune cells may play a vital role in the development of cardiovascular disease. In this study, researchers demonstrated that PCSK9 inhibition reversed the effect of oxidized LDL on immune activation.

Magic™ Humanized PCSK9 Immune Checkpoint Knock-In MiceFig.1. Anti-PCSK9 Mechanism of Action (Watts, 2016).

Development of Humanized PCSK9 Immune Checkpoint Knock-In Mice

Scientists in Creative Biolabs spare no efforts developing variety of well-characterized Magic™ “humanized” animal models containing a range of key immune checkpoint knock-in mouse models, which allows the in vivo evaluation of specific human biological therapies with fully functioning murine immune systems. Magic™ humanized mice including humanized PCSK9 knock-in mouse created by CRISPR/Cas9 gene editing are ready to directly evaluate anti-human PCSK9 antibodies in vivo before moving to successful human clinical trials. Please feel free to contact us for more detailed information.

Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:

Reference

  1. Watts GF. (2016). PCSK9 inhibitors - mechanisms of action. Aust Prescr 39:164-7.

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