The Transferrin receptor (TFRC) gene encodes Transferrin Receptor 1 (TFR1), a protein that is expressed at low levels in most normal cells but shows increased expression in highly proliferative cells, such as basal epidermal cells, intestinal epithelium, and certain activated immune cells. Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), also express this receptor at high levels ^[1]. TFR1 plays a critical role in maintaining iron metabolism and homeostasis by facilitating receptor-mediated endocytosis of iron-bound transferrin (Tf) via Tf cycling, thereby promoting iron uptake ^[2]. Cellular iron deficiency can lead to apoptosis, while cellular transformation requires substantial iron to sustain proliferation, with iron overload contributing to tumor progression. The high expression of TFR1 in many tumors makes it a potential tumor marker, offering a target for therapies to inhibit tumor growth and metastasis ^[1]. Moreover, TFR1 is implicated in anemia and iron metabolism disorders. Studies have shown that elevated TFR1 expression in cardiomyocytes is associated with exacerbated inflammation in myocarditis patients ^[3]. Various clinical drugs targeting TFR1 are currently under development, including antisense oligonucleotides (ASOs), antibody-drug conjugates (ADCs), and antibody-oligonucleotide conjugates, applicable to diseases such as cancer, anemia, and neurodegenerative disorders. Research indicates that enhancing antibody transport across the blood-brain barrier via TFR1, by forming specific bispecific antibodies with anti-β-amyloid antibodies, can improve therapeutic outcomes in Alzheimer's patients ^[4-5]. As research progresses, TFR1 is expected to become an effective clinical target for multiple diseases and a synergistic target for drug delivery across the blood-brain barrier (BBB). Parkinson's disease (PD) is a neurodegenerative disease with a high prevalence mainly in the middle-aged and elderly population. It is the second most common neurodegenerative disease after Alzheimer's disease (AD). The main clinical symptoms include resting tremors, limb stiffness, bradykinesia, loss of voluntary movement, etc. The typical pathological process of PD is the formation of Lewy bodies (LB) in the central nervous system (CNS), which results in the gradual death and loss of dopaminergic neurons, leading to the disease ^[6-7]. The main components of Lewy bodies are insoluble aggregates of abnormal α-synuclein (α-syn), and the SNCA gene, which encodes α-synuclein, is one of the key causative genes in Parkinson's disease. Mutations in this gene cause overexpression of α-syn, leading to the formation of Lewy bodies, ultimately leading to PD ^[8]. In addition, SNCA mutations are also associated with diseases such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). B6-huTFRC/huSNCA(3'UTR) mice are a dual-gene humanized model generated by crossing B6-huTFRC mice (Catalog No.: C001860) with B6-hSNCA (3'UTR) mice (Catalog No.: C001698). This model can be used for research on neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), as well as iron metabolism disorders and tumorigenesis and development. It is also applicable for the development of TFRC/SNCA-targeted drugs.

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]. Apolipoprotein E (ApoE) is a lipid particle-associated polymorphic carrier protein encoded by the APOE gene. It is a core component of plasma lipoproteins, participating in the production, transport, and clearance of lipoproteins. ApoE is associated with chylomicrons, chylomicron remnants, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL), especially showing preferential binding to HDL ^[7]. ApoE is the most important lipid transport protein in the body, having a profound impact on lipid metabolism. The interaction of ApoE with the low-density lipoprotein receptor (LDLR) is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins ^[8]. In peripheral tissues, ApoE is primarily produced by the liver and macrophages and mediates cholesterol metabolism. In the central nervous system, ApoE is produced mainly by astrocytes and is the major cholesterol carrier in the brain. ApoE is essential for transporting cholesterol from astrocytes to neurons ^[7-10]. In addition, ApoE forms a complex with activated C1q, becoming a checkpoint inhibitor target of the classical complement pathway ^[11]. Polymorphisms of the APOE are associated with Alzheimer's disease and lipid accumulation, hyperlipidemia, atherosclerosis, high cholesterolemia, etc., and are related to the risk of various cardiovascular diseases. The B6-hPCSK9/Apoe KO mice are obtained by crossing B6-hPCSK9 mice (Catalog No.: C001617) with B6J-Apoe KO mice (Catalog No.: C001507). B6J-Apoe KO mice exhibit elevated cholesterol levels and spontaneous atherosclerosis phenotypes due to the disruption of ApoE protein synthesis, further exacerbated under a high-fat diet (HFD). On the other hand, B6-hPCSK9 mice have the mouse Pcsk9 gene sequence replaced with the human PCSK9 gene sequence through gene editing technology, expressing the human PCSK9 protein. They can be used for the development of PCSK9-targeted drugs in hyperlipidemia, stroke, coronary heart disease, and other atherosclerotic cardiovascular diseases (ASCVD). The B6-hPCSK9/Apoe KO mice, while expressing the human PCSK9 protein, exhibit significantly elevated cholesterol levels and spontaneous atherosclerosis characteristics. These mice provide an ideal platform for the PCSK9-targeted drug development in hyperlipidemia and cardiovascular diseases, demonstrating good clinical and pathological relevance.

Hepatolenticular degeneration (HLD), also known as Wilson disease (WD), is an autosomal recessive copper transport disorder that can lead to liver failure. The incidence rate is about 1:30,000 ^[1]. The clinical manifestations of HLD mainly include chronic liver damage, and neurological and psychiatric symptoms, and can occasionally cause acute liver failure and hemolytic anemia. Its typical manifestation is the combination of liver disease and movement disorders in adolescence or early adulthood, but there is a large variation in phenotypic differences among patients, and up to 60% of patients have neurological or psychiatric symptoms ^[2]. Studies have shown that mutations in the ATP7B gene are associated with HLD. The characteristic feature is that with the loss of functional ATP7B protein, the clearance of excess copper is affected, leading to copper accumulation to toxic levels, damaging tissues and organs such as the liver and brain ^{[1, 3-4]}. The copper ion transport ATPase β-peptide encoded by the ATP7B gene is a member of the P-type cation transport ATPase family. This family uses the energy stored in ATP to transport metals into and out of cells. The ATP7B protein consists of multiple transmembrane domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites ^[5]. This protein mainly exists in the liver, with small amounts found in the kidneys and brain. Its function as a copper transport ATPase plays a role in transporting copper from the liver to other parts of the body. More than 900 pathogenic mutations of the ATP7B gene have been reported, with the mutation types mainly concentrated in missense, nonsense, or frameshift mutations, and other mechanisms include exon skipping, large deletions, and intron variations. The most common mutation in patients from Northern and Eastern Europe is H1069Q, but its frequency varies greatly among countries ^[2]. Hepatolenticular degeneration (HLD) treatments are mainly categorized into pharmacotherapy and surgical intervention. Pharmacotherapy is aimed at alleviating symptoms, preventing disease progression, and preventing complications, while surgery is typically liver transplantation. With the continuous exploration of the genetic etiology of Wilson’s disease, targeted gene therapy is expected to become the next "star therapy." Currently, multiple biotechnology companies and research institutions, including Prime Medicine and LogicBio Therapeutics, are developing a variety of gene editing therapies based on CRISPR/Cas9, Prime Editor, or other technologies to correct mutations in the ATP7B gene or replace the mutated ATP7B gene as a whole. These highly promising therapies are currently in preclinical studies ^[6-15]. Given that these gene editing therapies require precise targeting of the human ATP7B gene, humanizing mouse genes will help accelerate the entry of gene therapy into the clinical stage. This strain is a humanized point mutation model constructed by introducing the common pathogenic mutation p.H1069Q (CAC>CAA) into the humanized ATP7B gene of B6-hATP7B mice (Catalog No.: I001130). This model is suitable for studying the pathogenic mechanisms of Wilson's disease, and homozygous animals are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on this strain and provide customized services to meet the experimental needs.