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 mice are a humanized model generated by gene editing technology to replace the mouse Pcsk9 gene with the human PCSK9 gene sequence. These mice express human PCSK9 protein and can be used for research on various metabolic diseases, neurodegenerative diseases, tumor development, autoimmune disease mechanisms, and for the preclinical pharmacological evaluation of PCSK9-targeted drugs. In addition, Cyagen has developed a similar model, the B6-hPCSK9(CDS) mouse (PCSK9 coding sequence humanized model, Catalog Number: C001593). Compared to the B6-hPCSK9 mouse model, the B6-hPCSK9(CDS) mouse expresses higher levels of human PCSK9 and exhibits LDLR protein expression closer to physiological levels. It is recommended to choose the appropriate model based on the type of drug or research direction.

Lipoprotein A (LPA) is a type of particle similar to low-density lipoprotein (LDL) that is considered one of the risk factors for cardiovascular disease (CVD), such as atherosclerosis, coronary heart disease, stroke, etc ^[1]. LP(a) is similar in size and lipid content to LDL (low-density lipoprotein) and also contains the lipoprotein ApoB-100. However, unlike LDL, LP(a) additionally contains a variable-length lipoprotein called Apo(a), which covalently binds to ApoB-100 through a single disulfide bond. LP(a) plays an important role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and leading to smooth muscle cell proliferation. Furthermore, it is involved in wound healing and tissue repair, interacting with the components of blood vessel walls and the extracellular matrix ^[2]. However, LP(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating the formation of blood clots, and thereby triggering a series of pathological changes related to coronary heart disease, cardiovascular disease, atherosclerosis, thrombus formation, and stroke ^[3]. The plasma concentration of LP(a) is closely related to genetic factors and is primarily regulated by the LPA gene. Therefore, the LPA gene is an important potential target for cardiovascular disease treatment. The LPA gene encodes a serine protease that inhibits the activity of tissue-type plasminogen activator I. Fragments of this protein, generated through protein hydrolysis, can adhere to atherosclerotic lesions in arteries, promoting blood clot formation. The LPA gene is expressed in both humans and non-human primates but is not expressed in mice. Constructing mouse models expressing the human LPA gene is of significant importance for developing lipid-lowering drugs, which can drive the development of novel therapies for cardiovascular diseases. Currently, various novel therapies targeting the transcription rate of the LPA gene are under development, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) ^[4]. This strain was generated by mating B6-hLPA(CKI) mice (catalog number: C001521) with Alb-Cre mice (liver-specific Cre-expressing mice), resulting in a mouse model with liver-specific overexpression of the human LPA gene. B6-hLPA(CKI)/Alb-cre mice can be used to study the relationship between the LPA gene and hyperlipidemia and related cardiovascular diseases.

Lipoprotein A (LPA) is a type of particle similar to low-density lipoprotein (LDL) that is considered one of the risk factors for cardiovascular disease (CVD), such as atherosclerosis, coronary heart disease, stroke, etc ^[1]. LP(a) is similar in size and lipid content to LDL (low-density lipoprotein) and also contains the lipoprotein ApoB-100. However, unlike LDL, LP(a) additionally contains a variable-length lipoprotein called Apo(a), which covalently binds to ApoB-100 through a single disulfide bond. LP(a) plays an important role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and leading to smooth muscle cell proliferation. Furthermore, it is involved in wound healing and tissue repair, interacting with the components of blood vessel walls and the extracellular matrix ^[2]. However, LP(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating the formation of blood clots, and thereby triggering a series of pathological changes related to coronary heart disease, cardiovascular disease, atherosclerosis, thrombus formation, and stroke ^[3]. The plasma concentration of LP(a) is closely related to genetic factors and is primarily regulated by the LPA gene. Therefore, the LPA gene is an important potential target for cardiovascular disease treatment. The LPA gene encodes a serine protease that inhibits the activity of tissue-type plasminogen activator I. Fragments of this protein, generated through protein hydrolysis, can adhere to atherosclerotic lesions in arteries, promoting blood clot formation. The LPA gene is expressed in both humans and non-human primates but is not expressed in mice. Constructing mouse models expressing the human LPA gene is of significant importance for developing lipid-lowering drugs, which can drive the development of novel therapies for cardiovascular diseases. Currently, various novel therapies targeting the transcription rate of the LPA gene are under development, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) ^[4]. 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 ^[5]. 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 ^[6]. PCSK9 has emerged as a key 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 ^[7-8]. 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 ^[9-10]. The B6-hLPA (CKI)/Alb-cre/hPCSK9 mouse model is generated by crossing B6-hLPA (CKI) mice (Catalog No.: C001521, a mouse strain with conditional expression of the human LPA gene), Alb-Cre mice (liver-specific Cre-expressing mice), and B6-hPCSK9 mice (Catalog No.: C001617). This model harbors two cardiovascular disease risk factors, namely Lp (a) (lipoprotein (a)) and PCSK9, making it suitable for research on hyperlipidemia, stroke, coronary heart disease, and other atherosclerotic cardiovascular diseases (ASCVD).

Asialoglycoprotein receptor 1 (ASGR1), encoded by the ASGR1 gene, is central to cholesterol homeostasis and liver pathophysiology. Primarily localized to the hepatocyte plasma membrane, ASGR1 mediates ligand internalization and lysosomal degradation ^[1-2]. Ligand binding triggers ASGR1-dependent metabolism, involving the formation of a heteromeric complex with ASGR2, which recognizes glycoproteins with terminal galactose or N-acetylgalactosamine residues. Through modulation of the liver X receptor (LXR)/breast cancer susceptibility gene 1 (BRCA1)/BRCA1-associated ring domain protein 1 (BARD1) pathway, ASGR1 facilitates cholesterol excretion into bile, thereby influencing systemic lipid levels ^[1-2]. Beyond cholesterol regulation, ASGR1 participates in liver lesion processes, underscoring its broader role in liver health ^[3]. Notably, loss-of-function mutations in ASGR1 correlate with reduced circulating cholesterol and decreased cardiovascular disease risk. Conversely, elevated serum soluble ASGR1 (sASGR1) levels are associated with increased low-density lipoprotein cholesterol (LDL-C), particularly in hypertensive individuals ^[3]. Consequently, ASGR1 has emerged as a therapeutic target for cardiovascular and hepatic disorders, including hypercholesterolemia, atherosclerosis, non-alcoholic fatty liver disease, and cirrhosis ^[2-4]. The B6-huASGR1 mouse model was generated by replacing sequences from the ATG start codon to the TAG stop codon of the endogenous mouse Asgr1 gene with the sequences from the ATG start codon to the TAA stop codon of the human ASGR1 gene. This model can be used to study the pathological mechanisms and therapeutic approaches for cardiovascular and liver diseases, as well as for the development of ASGR1-targeted drugs.

The KLB gene encodes β-Klotho, a transmembrane protein that functions as an obligate co-receptor for fibroblast growth factor (FGF) receptors, specifically for the endocrine FGF ligands FGF19 and FGF21 ^[1]. Expressed across metabolic tissues, including adipose, liver, and pancreas, KLB is a critical regulator of FGF19 and FGF21 signaling, impacting glucose homeostasis, energy balance, and bile acid metabolism ^[1-3]. β-Klotho facilitates FGF19 and FGF21 signaling through direct interaction with FGF receptors ^[1]. KLB gene expression is observed across various tissues, encompassing metabolic, haematopoietic, foetal, and adult tissues ^[1]. Perturbations in KLB function and genetic variants have been implicated in a range of disorders, including hypogonadotropic hypogonadism, male infertility, obesity, non-alcoholic fatty liver disease, irritable bowel syndrome, and potentially certain malignancies ^[1-4]. Thus, KLB emerges as a pivotal gene in FGF signaling, exerting pleiotropic effects on metabolic physiology and disease ^[1-4]. The B6-hKLB mouse is a humanized model generated using gene editing technology by integrating the Chimeric cDNA and the 3'UTR of the mouse Klb gene into the mouse Klb gene locus. The mouse Klb endogenous extracellular domain was replaced with the human KLB domain, and the murine transmembrane-cytoplasmic region was remained. Homozygous B6-hKLB mice are viable and fertile. This model can be used for research on the pathological mechanisms and treatment methods of metabolic diseases such as obesity, diabetes, metabolic-associated steatohepatitis (MASH), inflammatory diseases, and potentially selected malignancies and the development of KLB-targeted drugs.

The FGFR1 gene encodes fibroblast growth factor receptor 1 (FGFR1), a pivotal transmembrane receptor tyrosine kinase widely expressed across diverse cell types, including epithelial, mesenchymal, and neuronal lineages, playing fundamental roles in development, angiogenesis, cell proliferation, differentiation, and migration through activation of intracellular signaling cascades like MAPK/ERK, PI3K/AKT, and STAT ^[1]. Aberrant FGFR1 expression or mutations are associated with developmental syndromes and various cancers, driving tumor growth, metastasis, and therapeutic resistance; its expression is tightly regulated by diverse cellular signals ^[2]. A key splice isoform is FGFR1c, predominantly expressed in epithelial cells and characterized by a specific extracellular immunoglobulin-like domain III, conferring high-affinity binding to a subset of FGF ligands crucial for epithelial-mesenchymal interactions during development and adult tissue homeostasis ^[3]. Dysregulation of FGFR1c signaling is implicated in the pathogenesis of cancers such as breast, prostate, and lung carcinomas, contributing to tumor initiation, progression, angiogenesis, and potentially therapy resistance, highlighting the importance of understanding isoform-specific functions for targeted therapeutic interventions ^[3-4]. B6-hFGFR1c mice are humanized models generated by gene editing technology, in which the p.22R to partial intron 2 of the mouse Fgfr1 gene was replaced in situ with p.22R to 376E from the coding sequence of the human FGFR1 gene, p.377I to 823X from the coding sequence of the mouse Fgfr1 gene, and the 3'UTR of the mouse Fgfr1 gene. This model can be used to study the pathological mechanisms and therapeutic methods of cancers, metabolic diseases such as obesity, diabetes, and metabolic-associated steatohepatitis (MASH), as well as the screening and development of FGFR1c-targeted drugs, and preclinical efficacy and safety evaluations.

The activin A receptor type 1C (ACVR1C), also known as activin receptor-like kinase 7 (ALK7), is a crucial type I serine/threonine kinase receptor belonging to the transforming growth factor-β (TGF-β) superfamily signaling pathway. Upon binding ligands such as activin AB, activin B, and NODAL, ACVR1C initiates intracellular signaling cascades by phosphorylating downstream SMAD2 and SMAD3 transcription factors, thereby regulating diverse cellular processes including cell differentiation, proliferation, apoptosis, and metabolic homeostasis ^[1]. ACVR1C exhibits a broad expression profile across various tissues, with notable enrichment in adipose tissue, pancreas, heart, and specific brain regions, suggesting its pleiotropic roles in maintaining tissue function ^[2]. Dysregulation of ACVR1C signaling has been implicated in a range of metabolic disorders, including obesity and type 2 diabetes, as well as in the pathogenesis of certain cancers like retinoblastoma, highlighting its significance as a potential therapeutic target for these conditions ^[3]. The B6-hALK7 (hACVR1C) mouse is a humanized model constructed using gene editing technology, where the region from aa.27 in exon 2 to partial intron 2 of mouse Acvr1c was replaced with "ACVR1C chimeric CDS-WPRE-BGH pA" cassette. The murine signal peptide of Acvr1c was preserved. This model can be used for studying the pathological mechanisms and therapeutic approaches of metabolic disorders such as obesity and type 2 diabetes, and certain cancers like retinoblastoma, and for the development of ACVR1C-targeted drugs.

Lipoprotein A (LPA) is a type of particle similar to low-density lipoprotein (LDL) that is considered one of the risk factors for cardiovascular disease (CVD) such as atherosclerosis, coronary heart disease, stroke, etc ^[1]. LP(a) is similar in size and lipid content to LDL (low-density lipoprotein) and contains the lipoprotein ApoB-100. However, unlike LDL, LP(a) contains a variable-length lipoprotein called Apo(a), which covalently binds to ApoB-100 through a single disulfide bond. LP(a) plays an important role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and leading to smooth muscle cell proliferation. Furthermore, it is involved in wound healing and tissue repair, interacting with the components of blood vessel walls and the extracellular matrix ^[2]. However, LP(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating the formation of blood clots, and thereby triggering a series of pathological changes related to coronary heart disease, cardiovascular disease, atherosclerosis, thrombus formation, and stroke ^[3]. The plasma concentration of LP(a) is closely related to genetic factors and is primarily regulated by the LPA gene. Therefore, the LPA gene is an important potential target for cardiovascular disease treatment. The LPA gene encodes a serine protease that inhibits the activity of tissue-type plasminogen activator I. Fragments of this protein, generated through protein hydrolysis, can adhere to atherosclerotic lesions in arteries, promoting blood clot formation. The LPA gene is expressed in both humans and non-human primates but is not expressed in mice. Constructing mouse models expressing the human LPA gene is of significant importance for developing lipid-lowering drugs, which can drive the development of novel therapies for cardiovascular diseases. Currently, various novel therapies targeting the transcription rate of the LPA gene are under development, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) ^[4]. This strain was a conditional mouse model expressing the human LPA gene, where the ‘loxP-Stop-loxP-hLPA’ sequence was inserted into the intron 1 of the ROSA26 safe harbor locus. When this model is bred with tool mice expressing Cre recombinase, sequence recombination occurs in the Cre-positive cells and tissues of the offspring mice. After the Cre-recombinase-mediated deletion of the stop element (LSL), specific expression of the human LPA gene can be achieved. The B6-hLPA(CKI) mice can be used for research related to atherosclerosis, and thrombotic cardiovascular diseases, as well as the development, screening, and preclinical evaluation of human LPA gene-targeted drugs.

The Growth Differentiation Factor 15 (GDF15) gene encodes a secreted ligand of the Transforming Growth Factor-β (TGF-β) superfamily protein. This protein plays a crucial role in the TGFβ signaling pathway, which is integral to various cellular processes ^[1]. GDF15 is involved in the body’s response to stress following cell damage. It is associated with tissue hypoxia, inflammation, acute injury, and oxidative stress, among other disease states. Elevated levels of GDF15 in the serum are considered a potential biomarker for the progression of cancer, as it is overexpressed in various types of tumor cells, including colon, prostate, pancreatic, breast, and thyroid cancers ^[2-3]. Interestingly, GDF15 is not solely a pathological biomarker. Despite its association with disease states, it also exhibits high expression under various non-pathological conditions. Studies suggest that GDF15 may exert a protective effect on the heart, liver, kidney, and lungs following inflammation and injury, highlighting its potential role in tissue repair and recovery ^[4]. GDF15 is an important biomarker for metabolic diseases, cardiovascular diseases, tumors, and more, and holds potential as a therapeutic target. It can induce anorexia by activating the GFRAL-RET receptor in the brainstem, making it a promising target for anti-obesity therapy ^[5]. Furthermore, GDF15 neutralization could potentially alleviate anorexia and weight loss, common side effects of platinum-based chemotherapy ^[6]. Research has shown that a therapeutic antagonistic monoclonal antibody can inhibit RET signal transduction by blocking the interaction between GDF15-driven RET and cell surface GFRAL. This could reverse excessive lipid oxidation in tumor-bearing mice and prevent cancer cachexia ^[7]. The potential of GDF15 as a therapeutic target is being increasingly recognized in the scientific community. In this context, the construction of animal gene humanization models for this target is of significant importance, providing a crucial tool for further research and development in this area. This strain is a mouse Gdf15 gene humanized model expressing human GDF15 protein obtained by replacing the sequence encoding the endogenous structural domain in the mouse Gdf15 gene with the sequence encoding the structural domain in the human GDF15 gene. B6-hGDF15 mice can be used for research on metabolic diseases, cardiovascular diseases, tumor occurrence and development, etc., to assist in the preclinical evaluation of GDF15-targeted drugs.

The DPP4 gene (CD26) encodes dipeptidyl peptidase 4, an intrinsic type II transmembrane glycoprotein and a serine exopeptidase involved in glucose and insulin metabolism and immune regulation. The DPP4 protein is a functional receptor for the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The spike protein of MERS-CoV binds to DPP4, mediating the virus's attachment to host cells and promoting virus-cell fusion, thereby initiating infection ^[1-2]. Studies have found that the DPP4 protein may interact with the S1 domain of the spike glycoprotein of COVID-19, aiding in enhancing the transmission efficiency of viral particles ^[3]. Experimental evidence has shown that hDPP4 transgenic mice infected with MERS-CoV experience high mortality and severe pneumonia ^[4]. These mice infected with Manis javanica HKU4-related coronavirus (MjHKU4r-CoV-1) develop mild to moderate pulmonary histological damage ^[5]. Thus, gene-edited mice expressing human DPP4 protein are important tools for studying coronavirus infections. Additionally, DPP4 expression is severely dysregulated in diseases such as inflammation, cancer, obesity, and diabetes. DPP4 is highly expressed in the intestine, where it selectively cleaves N-terminal dipeptides from various substrates, including incretins, to inactivate multiple bioactive peptides. Since incretins like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are crucial for regulating postprandial insulin secretion, inhibiting DPP4 to elevate endogenous GLP-1 and GIP levels to increase insulin levels has become an important treatment method for type 2 diabetes (T2D) ^[6]. The B6-hDPP4(line 1) mouse is a humanized model constructed by gene editing technology to replace a partial region of the mouse Dpp4 gene with the human DPP4 gene CDS sequence. This model can be used to study the infection mechanisms of viruses such as MERS-CoV and COVID-19, as well as to develop related virus vaccines. Additionally, this model can be utilized to develop DPP4 inhibitor therapies. Additionally, Cyagen Biosciences has developed B6-hDPP4(line 2) mice (Catalog ID: I001188) on the C57BL/6JCya background strain and BALB/c-hDPP4(line 2) mice (Catalog ID: I001189) on the BALB/cAnCya background strain. These two models replace the mouse Dpp4 gene p.S29 to part of intron 2 with the "Human DPP4 CDS-rBG pA" expression cassette, meeting the experimental needs for different strain backgrounds.