B6-hPCSK9 (CDS) Mouse

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a serine protease primarily produced in the liver but expressed in other tissues, including the intestine, heart, and neurons. The N-terminal domain of the PCSK9 protein is responsible for protein localization and stability, while the C-terminal domain is responsible for protein enzymatic activity ^[1]. The Low-density lipoprotein receptor (LDLR) is a receptor that is responsible for clearing low-density lipoprotein cholesterol (LDL-C) from the blood. PCSK9 cleaves the intracellular domain of LDLR on the cell surface, causing it to detach from the cell membrane and be transported to the lysosome for degradation, promoting LDLR degradation, and increasing plasma LDL-C. Overexpression or gain-of-function mutations of the PCSK9 gene can lead to LDL-C accumulation by reducing LDLR levels. This can cause hypercholesterolemia, which increases the risk of cardiovascular diseases, such as atherosclerosis and coronary heart disease, and neurodegenerative diseases, such as Alzheimer's disease ^[2]. PCSK9 has become an important target for the development of lipid-lowering drugs. Several PCSK9-targeted antibodies or small nucleic acid drugs have been approved for marketing worldwide, including evolocumab from Amgen, alirocumab from Sanofi and Regeneron, and inclisiran from Novartis. These drugs primarily work by inhibiting PCSK9 activity or preventing PCSK9 protein from binding to LDLR, lowering LDL-C levels in the blood to treat hypercholesterolemia ^[3-4]. In addition, PCSK9 can promote tumor growth and development by regulating cell proliferation, migration, and invasion. It can also regulate the expression of inflammatory factors that contribute to inflammation. Therefore, targeting the expression of PCSK9 has been investigated in tumor immunotherapy and autoimmune disease therapy ^[5-6].

B6-hPCSK9(CDS) mice are generated by integrating the human PCSK9 protein coding sequence (CDS) and 3' untranslated region (UTR) into the mouse Pcsk9 gene locus using gene editing techniques, resulting in a model expressing human PCSK9 protein while disrupting the expression of the mouse endogenous Pcsk9 gene. These mice can be used to study various metabolic diseases, neurodegenerative diseases, tumor development, and autoimmune diseases, as well as for the development, screening, and preclinical pharmacological evaluation of PCSK9-targeted drugs. Compared to the similar B6-hPCSK9 mice (PCSK9 genomic humanized model, Catalog Number: C001617), B6-hPCSK9(CDS) mice have higher levels of human PCSK9 protein expression in serum, while LDLR expression is closer to the normal endogenous levels in mice.