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B6-huTFRC/huSNCA(3'UTR)
Product ID:
C001873
Strain:
C57BL/6NCya
Status:
Description:
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.
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.
B6-hIL2RA
Product ID:
C001713
Strain:
C57BL/6NCya
Status:
Description:
The interleukin-2 receptor alpha subunit, encoded by the IL2RA gene and also known as CD25, is a critical determinant of IL-2 signaling, a pathway fundamental to T cell biology. While CD25 alone exhibits low affinity for IL-2, its assembly with the IL-2 receptor beta and gamma chains forms the high-affinity receptor complex essential for robust cellular responses to this pleiotropic cytokine [1]. Expressed prominently on activated T lymphocytes, including effector and regulatory T cells, CD25 is pivotal for diverse processes such as T cell proliferation, differentiation, and the maintenance of immune tolerance, largely mediated through its indispensable role in regulatory T cell development and function [2]. Consequently, perturbations in IL2RA expression or genetic variants within the locus are strongly associated with susceptibility to a range of severe autoimmune disorders, including multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, highlighting its central involvement in immune homeostasis breakdown [3]. Furthermore, aberrant CD25 expression has been observed in certain malignancies, suggesting roles beyond adaptive immunity [4]. The demonstrable impact of IL2RA on immune regulation and disease pathogenesis underscores its significance as a key molecule in immunology and a compelling target for therapeutic intervention.
The B6-hIL2RA mouse is a humanized model constructed by replacing the sequence of the mouse Il2ra endogenous extracellular domain in situ with the corresponding extracellular domain from the human IL2RA. The murine signal peptide and transmembrane-cytoplasmic region were preserved. The B6-hIL2RA mice can be used for the study of the pathogenesis of autoimmune diseases such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, and certain malignancies, as well as for IL2RA-targeted drug development.
The interleukin-2 receptor alpha subunit, encoded by the IL2RA gene and also known as CD25, is a critical determinant of IL-2 signaling, a pathway fundamental to T cell biology. While CD25 alone exhibits low affinity for IL-2, its assembly with the IL-2 receptor beta and gamma chains forms the high-affinity receptor complex essential for robust cellular responses to this pleiotropic cytokine [1]. Expressed prominently on activated T lymphocytes, including effector and regulatory T cells, CD25 is pivotal for diverse processes such as T cell proliferation, differentiation, and the maintenance of immune tolerance, largely mediated through its indispensable role in regulatory T cell development and function [2]. Consequently, perturbations in IL2RA expression or genetic variants within the locus are strongly associated with susceptibility to a range of severe autoimmune disorders, including multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, highlighting its central involvement in immune homeostasis breakdown [3]. Furthermore, aberrant CD25 expression has been observed in certain malignancies, suggesting roles beyond adaptive immunity [4]. The demonstrable impact of IL2RA on immune regulation and disease pathogenesis underscores its significance as a key molecule in immunology and a compelling target for therapeutic intervention.
The B6-hIL2RA mouse is a humanized model constructed by replacing the sequence of the mouse Il2ra endogenous extracellular domain in situ with the corresponding extracellular domain from the human IL2RA. The murine signal peptide and transmembrane-cytoplasmic region were preserved. The B6-hIL2RA mice can be used for the study of the pathogenesis of autoimmune diseases such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, and certain malignancies, as well as for IL2RA-targeted drug development.
B6-hBAFFR (hTNFRSF13C)
Product ID:
C001711
Strain:
C57BL/6NCya
Status:
Description:
The gene TNFRSF13C encodes the B cell-activating factor receptor (BAFF-R), also known as BLyS receptor 3 (BR3) or CD268. As a member of the tumor necrosis factor receptor superfamily (TNFRSF), BAFF-R functions as a crucial type III transmembrane signaling protein on lymphocytes. Its expression is predominantly observed on the surface of B cells throughout various stages of their development, from transitional to mature naive and memory populations, underscoring its vital role in peripheral B cell homeostasis [1]. BAFF-R serves as the primary receptor for the cytokine BAFF (TNFSF13B), and their interaction delivers essential survival and maturation signals to B cells, mediated through downstream pathways including the activation of NF-κB and PI3K. Genetic alterations in TNFRSF13C, including point mutations and deletions, or dysregulation of the BAFF-BAFF-R axis, are increasingly recognized for their contribution to immune pathology [2]. Such aberrations are associated with primary immunodeficiencies like common variable immunodeficiency (CVID), characterized by profound defects in antibody production and recurrent infections, as well as a range of autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren's syndrome, and certain B cell malignancies [2-3]. The critical, non-redundant function of BAFF-R in B cell biology highlights its significance as a key node in adaptive immunity and positions the BAFF-BAFF-R pathway as a compelling target for therapeutic intervention in a spectrum of immune-mediated disorders.
The B6-hBAFFR (hTNFRSF13C) mouse is a humanized model constructed by replacing the sequence of the mouse Tnfrsf13c endogenous extracellular domain in situ with the corresponding extracellular domain from the human TNFRSF13C. The B6-hBAFFR (hTNFRSF13C) mice can be used for the study of the pathogenesis of immune-mediated disorders such as common variable immunodeficiency (CVID), systemic lupus erythematosus (SLE), and Sjögren's syndrome, and certain B cell malignancies, as well as for TNFRSF13C-targeted drug development.
The gene TNFRSF13C encodes the B cell-activating factor receptor (BAFF-R), also known as BLyS receptor 3 (BR3) or CD268. As a member of the tumor necrosis factor receptor superfamily (TNFRSF), BAFF-R functions as a crucial type III transmembrane signaling protein on lymphocytes. Its expression is predominantly observed on the surface of B cells throughout various stages of their development, from transitional to mature naive and memory populations, underscoring its vital role in peripheral B cell homeostasis [1]. BAFF-R serves as the primary receptor for the cytokine BAFF (TNFSF13B), and their interaction delivers essential survival and maturation signals to B cells, mediated through downstream pathways including the activation of NF-κB and PI3K. Genetic alterations in TNFRSF13C, including point mutations and deletions, or dysregulation of the BAFF-BAFF-R axis, are increasingly recognized for their contribution to immune pathology [2]. Such aberrations are associated with primary immunodeficiencies like common variable immunodeficiency (CVID), characterized by profound defects in antibody production and recurrent infections, as well as a range of autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren's syndrome, and certain B cell malignancies [2-3]. The critical, non-redundant function of BAFF-R in B cell biology highlights its significance as a key node in adaptive immunity and positions the BAFF-BAFF-R pathway as a compelling target for therapeutic intervention in a spectrum of immune-mediated disorders.
The B6-hBAFFR (hTNFRSF13C) mouse is a humanized model constructed by replacing the sequence of the mouse Tnfrsf13c endogenous extracellular domain in situ with the corresponding extracellular domain from the human TNFRSF13C. The B6-hBAFFR (hTNFRSF13C) mice can be used for the study of the pathogenesis of immune-mediated disorders such as common variable immunodeficiency (CVID), systemic lupus erythematosus (SLE), and Sjögren's syndrome, and certain B cell malignancies, as well as for TNFRSF13C-targeted drug development.
B6-hMECP2*T158M
Product ID:
C001569
Strain:
C57BL/6NCya
Status:
Description:
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder primarily affecting female infants and young children, with an incidence of approximately 1 in 10,000 to 15,000 females. Characteristic clinical features include intellectual disability, loss of language skills, stereotypic hand movements, and gait disturbances. Affected individuals typically experience a period of normal development, followed by deceleration in head circumference growth between 6 to 18 months of age, and subsequent regression of acquired motor and cognitive abilities. Overt impairments in cognition and motor function generally emerge within 1 to 2 years. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are responsible for over 90% of RTT cases. MECP2 is a nuclear protein that binds methylated DNA to modulate gene transcription. MECP2 gene duplications lead to MECP2 duplication syndrome (MDS), while MECP2 deficiency disrupts central nervous system maturation, adversely affecting learning and memory, culminating in the clinical manifestations of RTT.
Current therapeutic strategies for RTT primarily revolve around gene supplementation using adeno-associated virus (AAV) vectors to deliver functional human MECP2 genes to compensate for the endogenous deficiency. However, the substantial size of the MECP2 gene surpasses the packaging capacity of most viral vectors, and overexpression of MECP2 poses a risk of severe neurological complications. These challenges have significantly impeded the progress of gene supplementation therapies. Consequently, the focus has shifted towards DNA/RNA editing approaches aimed at correcting MECP2 mutations and restoring physiological levels of MECP2 protein expression. Notably, several research groups have successfully employed CRISPR-based gene editing technologies to rectify MECP2 mutations in induced pluripotent stem cells (iPSCs) or patient-derived cells ex vivo [1-2]. Given the pivotal role of animal models in preclinical research, the development of humanized mouse models expressing the human MECP2 gene is crucial. These models facilitate the transition of gene therapy candidates—encompassing small nucleic acids, CRISPR-based editors, base editors, and RNA editing technologies—into clinical stages [3-4].
This strain is a humanized MECP2 gene mouse model, generated by replacing the endogenous mouse Mecp2 gene with the human MECP2 gene harboring the T158M mutation through embryonic stem cell targeting techniques. This mutation represents the most common human RTT-associated missense mutation in MECP2. Studies have shown that mice carrying this mutation recapitulate many clinical features of RTT [5].
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder primarily affecting female infants and young children, with an incidence of approximately 1 in 10,000 to 15,000 females. Characteristic clinical features include intellectual disability, loss of language skills, stereotypic hand movements, and gait disturbances. Affected individuals typically experience a period of normal development, followed by deceleration in head circumference growth between 6 to 18 months of age, and subsequent regression of acquired motor and cognitive abilities. Overt impairments in cognition and motor function generally emerge within 1 to 2 years. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are responsible for over 90% of RTT cases. MECP2 is a nuclear protein that binds methylated DNA to modulate gene transcription. MECP2 gene duplications lead to MECP2 duplication syndrome (MDS), while MECP2 deficiency disrupts central nervous system maturation, adversely affecting learning and memory, culminating in the clinical manifestations of RTT.
Current therapeutic strategies for RTT primarily revolve around gene supplementation using adeno-associated virus (AAV) vectors to deliver functional human MECP2 genes to compensate for the endogenous deficiency. However, the substantial size of the MECP2 gene surpasses the packaging capacity of most viral vectors, and overexpression of MECP2 poses a risk of severe neurological complications. These challenges have significantly impeded the progress of gene supplementation therapies. Consequently, the focus has shifted towards DNA/RNA editing approaches aimed at correcting MECP2 mutations and restoring physiological levels of MECP2 protein expression. Notably, several research groups have successfully employed CRISPR-based gene editing technologies to rectify MECP2 mutations in induced pluripotent stem cells (iPSCs) or patient-derived cells ex vivo [1-2]. Given the pivotal role of animal models in preclinical research, the development of humanized mouse models expressing the human MECP2 gene is crucial. These models facilitate the transition of gene therapy candidates—encompassing small nucleic acids, CRISPR-based editors, base editors, and RNA editing technologies—into clinical stages [3-4].
This strain is a humanized MECP2 gene mouse model, generated by replacing the endogenous mouse Mecp2 gene with the human MECP2 gene harboring the T158M mutation through embryonic stem cell targeting techniques. This mutation represents the most common human RTT-associated missense mutation in MECP2. Studies have shown that mice carrying this mutation recapitulate many clinical features of RTT [5].
B6-hCCR8
Product ID:
C001808
Strain:
C57BL/6NCya
Status:
Description:
The CCR8 gene encodes the C-C chemokine receptor type 8, a 41 kDa G-protein coupled receptor with seven transmembrane regions. This protein functions as a receptor for the chemokine CCL1 (also known as I-309) and is involved in cell migration, particularly for various immune cell types, and thymic cell apoptosis. CCR8 expression is notably found in the thymus and is also highly expressed on subsets of CD4+ memory T lymphocytes (including Th2 effector and regulatory T cells or Tregs), natural killer T (NKT) cells, macrophages, monocytes, and monocyte-derived dendritic cells [1]. Its expression is particularly relevant in inflammatory settings, where it guides immune cells to sites of inflammation and infection, such as in the lungs in asthma, and in the skin in atopic dermatitis [2]. Associated diseases and conditions include allergic disorders (like asthma and atopic dermatitis) due to its role in promoting Th2-biased immune responses, various cancers (e.g., malignant melanoma, hepatocellular carcinoma, cutaneous T-cell lymphomas) where it is highly expressed on tumor-infiltrating Tregs contributing to an immunosuppressive tumor microenvironment, and chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and potentially multiple sclerosis (MS) [3]. CCR8 also acts as an alternative co-receptor for HIV-1 infection [4].
The B6-hCCR8 mouse is a humanized model, constructed by replacing the coding sequences of the endogenous mouse Ccr8 gene with the coding sequences of the human CCR8 gene. B6-hCCR8 mice can be used for research into the pathogenesis of allergic disorders, various cancers, chronic inflammatory conditions, and HIV-1 infection, as well as for the screening, development, and safety evaluation of CCR8-targeted drugs.
The CCR8 gene encodes the C-C chemokine receptor type 8, a 41 kDa G-protein coupled receptor with seven transmembrane regions. This protein functions as a receptor for the chemokine CCL1 (also known as I-309) and is involved in cell migration, particularly for various immune cell types, and thymic cell apoptosis. CCR8 expression is notably found in the thymus and is also highly expressed on subsets of CD4+ memory T lymphocytes (including Th2 effector and regulatory T cells or Tregs), natural killer T (NKT) cells, macrophages, monocytes, and monocyte-derived dendritic cells [1]. Its expression is particularly relevant in inflammatory settings, where it guides immune cells to sites of inflammation and infection, such as in the lungs in asthma, and in the skin in atopic dermatitis [2]. Associated diseases and conditions include allergic disorders (like asthma and atopic dermatitis) due to its role in promoting Th2-biased immune responses, various cancers (e.g., malignant melanoma, hepatocellular carcinoma, cutaneous T-cell lymphomas) where it is highly expressed on tumor-infiltrating Tregs contributing to an immunosuppressive tumor microenvironment, and chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and potentially multiple sclerosis (MS) [3]. CCR8 also acts as an alternative co-receptor for HIV-1 infection [4].
The B6-hCCR8 mouse is a humanized model, constructed by replacing the coding sequences of the endogenous mouse Ccr8 gene with the coding sequences of the human CCR8 gene. B6-hCCR8 mice can be used for research into the pathogenesis of allergic disorders, various cancers, chronic inflammatory conditions, and HIV-1 infection, as well as for the screening, development, and safety evaluation of CCR8-targeted drugs.
B6-hATP7B*H1069Q
Product ID:
C001610
Strain:
C57BL/6NCya
Status:
Description:
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.
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.
B6-hTTR
Product ID:
C001512
Strain:
C57BL/6NCya
Status:
Description:
Transthyretin amyloidosis (ATTR) is a protein disorder caused by the abnormal accumulation of misfolded transthyretin (TTR) protein in organs and tissues throughout the body, primarily affecting the peripheral nervous system and heart [1]. ATTR can be divided into hereditary ATTR and wild-type ATTR, with hereditary ATTR being caused by genetic mutations in the TTR gene.
The TTR gene encodes transthyretin (TTR), also known as prealbumin, which is mainly synthesized in the liver and to a lesser extent in the brain’s choroid plexus or ocular photoreceptor tissue (such as the retina). TTR is a transport protein that exists as a homotetramer in peripheral blood under normal physiological conditions and participates in the transport of thyroxine and retinol-binding protein. Mutations in the TTR gene can lead to hereditary familial amyloidosis, such as Transthyretin Cardiac Amyloidosis Myocardiopathy (ATTR-CM) and Transthyretin Amyloid Polyneuropathy (ATTR-PN). The pathogenic mechanism is that structurally unstable TTR protein tetramers develop into pathological aggregates in tissues such as the peripheral nervous system, heart, eyes, kidneys, and meninges, forming insoluble amyloid deposits, eventually leading to ATTR.
The treatments for ATTR-CM and ATTR-PN mainly involve inhibiting the production of mutant TTR mRNA or stabilizing the structure of TTR protein tetramers. At present, various drug pipelines have emerged in the field of gene therapy targeting the TTR gene, including ASO, siRNA, and CRISPR-based gene therapies. Among them, Inotersen Sodium, developed by Ionis, the leading oligonucleic acid drug (ASO) therapy company, is the first approved ASO drug for this disease. It targets the conserved sequence of the 3’ untranslated region (UTR) of TTR mRNA to induce mRNA degradation and reduce TTR synthesis in liver cells [2]. Since most ASO, siRNA, and CRISPR-based therapies target human TTR genes, considering the differences between animals and humans at the genetic level, humanizing mouse genes will help advance gene therapy drug pipelines into clinical stages. This strain is a mouse Ttr gene humanized model and can be used for research on transthyretin amyloidosis. The homozygous B6-hTTR mice are viable and fertile [3-6]. Additionally, 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 for specific mutations to meet experimental needs in pharmacology.
Transthyretin amyloidosis (ATTR) is a protein disorder caused by the abnormal accumulation of misfolded transthyretin (TTR) protein in organs and tissues throughout the body, primarily affecting the peripheral nervous system and heart [1]. ATTR can be divided into hereditary ATTR and wild-type ATTR, with hereditary ATTR being caused by genetic mutations in the TTR gene.
The TTR gene encodes transthyretin (TTR), also known as prealbumin, which is mainly synthesized in the liver and to a lesser extent in the brain’s choroid plexus or ocular photoreceptor tissue (such as the retina). TTR is a transport protein that exists as a homotetramer in peripheral blood under normal physiological conditions and participates in the transport of thyroxine and retinol-binding protein. Mutations in the TTR gene can lead to hereditary familial amyloidosis, such as Transthyretin Cardiac Amyloidosis Myocardiopathy (ATTR-CM) and Transthyretin Amyloid Polyneuropathy (ATTR-PN). The pathogenic mechanism is that structurally unstable TTR protein tetramers develop into pathological aggregates in tissues such as the peripheral nervous system, heart, eyes, kidneys, and meninges, forming insoluble amyloid deposits, eventually leading to ATTR.
The treatments for ATTR-CM and ATTR-PN mainly involve inhibiting the production of mutant TTR mRNA or stabilizing the structure of TTR protein tetramers. At present, various drug pipelines have emerged in the field of gene therapy targeting the TTR gene, including ASO, siRNA, and CRISPR-based gene therapies. Among them, Inotersen Sodium, developed by Ionis, the leading oligonucleic acid drug (ASO) therapy company, is the first approved ASO drug for this disease. It targets the conserved sequence of the 3’ untranslated region (UTR) of TTR mRNA to induce mRNA degradation and reduce TTR synthesis in liver cells [2]. Since most ASO, siRNA, and CRISPR-based therapies target human TTR genes, considering the differences between animals and humans at the genetic level, humanizing mouse genes will help advance gene therapy drug pipelines into clinical stages. This strain is a mouse Ttr gene humanized model and can be used for research on transthyretin amyloidosis. The homozygous B6-hTTR mice are viable and fertile [3-6]. Additionally, 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 for specific mutations to meet experimental needs in pharmacology.
B6-hKHK
Product ID:
C001642
Strain:
C57BL/6NCya
Status:
Description:
The KHK gene encodes ketohexokinase, an enzyme mainly expressed in the liver, kidneys, and small intestine, and plays a crucial role in fructose metabolism. KHK catalyzes the phosphorylation of fructose into fructose-1-phosphate, which is the first step in the fructose metabolic pathway, enabling its conversion into intermediate products that can enter the glycolytic or gluconeogenic pathways. This gene generates two isoforms (KHK-A and KHK-C). Among them, KHK-C has higher catalytic activity and is mainly expressed in the liver, while KHK-A is widely distributed in various tissues, but its function is not fully understood. The expression and activity of KHK are closely related to fructose intake. Excessive fructose intake will lead to the upregulation of KHK activity, which triggers metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and obesity [1]. The excessive activation of KHK-C is closely associated with fructose-induced metabolic dysfunction, and blocking KHK-C can significantly ameliorate metabolic abnormalities in fructose-sensitive mice [2]. In addition, fructose metabolism may play an important role in cancer and other proliferative diseases, providing signaling cues that sustain the proliferation of cancer cells. Many cancer cells overexpress KHK. Moreover, the genetic disorder (essential fructosuria) caused by loss-of-function mutations in KHK is clinically asymptomatic and harmless, which further supports the view that inhibiting KHK in cancer patients may be well tolerated [3]. Therefore, KHK has emerged as a potential target for treating metabolic diseases and cancer. Inhibitors targeting KHK are currently under development and have shown the potential to improve metabolic syndrome and inhibit tumor progression.
The B6-hKHK mice are a humanized model constructed through gene editing technology, in which the sequence of the mouse Khk gene is replaced in situ with the corresponding sequence of the human KHK gene. Homozygous B6-hKHK mice are viable and fertile. This model can be used for the study of the pathological mechanisms and treatment methods of metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and obesity, as well as cancer. It can also be applied to the screening, research and development, and safety evaluation of KHK-targeted drugs.
The KHK gene encodes ketohexokinase, an enzyme mainly expressed in the liver, kidneys, and small intestine, and plays a crucial role in fructose metabolism. KHK catalyzes the phosphorylation of fructose into fructose-1-phosphate, which is the first step in the fructose metabolic pathway, enabling its conversion into intermediate products that can enter the glycolytic or gluconeogenic pathways. This gene generates two isoforms (KHK-A and KHK-C). Among them, KHK-C has higher catalytic activity and is mainly expressed in the liver, while KHK-A is widely distributed in various tissues, but its function is not fully understood. The expression and activity of KHK are closely related to fructose intake. Excessive fructose intake will lead to the upregulation of KHK activity, which triggers metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and obesity [1]. The excessive activation of KHK-C is closely associated with fructose-induced metabolic dysfunction, and blocking KHK-C can significantly ameliorate metabolic abnormalities in fructose-sensitive mice [2]. In addition, fructose metabolism may play an important role in cancer and other proliferative diseases, providing signaling cues that sustain the proliferation of cancer cells. Many cancer cells overexpress KHK. Moreover, the genetic disorder (essential fructosuria) caused by loss-of-function mutations in KHK is clinically asymptomatic and harmless, which further supports the view that inhibiting KHK in cancer patients may be well tolerated [3]. Therefore, KHK has emerged as a potential target for treating metabolic diseases and cancer. Inhibitors targeting KHK are currently under development and have shown the potential to improve metabolic syndrome and inhibit tumor progression.
The B6-hKHK mice are a humanized model constructed through gene editing technology, in which the sequence of the mouse Khk gene is replaced in situ with the corresponding sequence of the human KHK gene. Homozygous B6-hKHK mice are viable and fertile. This model can be used for the study of the pathological mechanisms and treatment methods of metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and obesity, as well as cancer. It can also be applied to the screening, research and development, and safety evaluation of KHK-targeted drugs.
B6-hFCGR1
Product ID:
C001500
Strain:
C57BL/6NCya
Status:
Description:
FCGR1 gene encodes FcγRI, a specific receptor for IgG antibodies, also known as CD64. This receptor plays a key role in human immune responses. FcγRI has a high affinity for the Fc portion of IgG antibodies and is the only member of the human FcγRs with a high affinity for monomeric IgG. It plays important roles in both innate and adaptive immune responses [1]. FcγRI is expressed on a variety of immune cells, including monocytes, macrophages, dendritic cells, and neutrophils. It plays a critical role in host defense against infection and humoral immunity by influencing processes such as phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and antigen presentation [2-3]. The binding of FcγRI to IgG-coated target cells promotes their phagocytosis by immune cells. This is an important mechanism for clearing infected cells, apoptotic cells, and other foreign particles. In addition, this binding can also promote the release of cytotoxic granules by immune cells, such as natural killer cells and cytotoxic T cells, leading to the killing and lysis of target cells. In antigen presentation, FcγRI binding to IgG-coated antigens promotes dendritic cells to take them up and present them to T cells, which is essential for the initiation of adaptive immune responses. In addition, FcγRI is involved in a variety of important physiological processes, such as wound healing and inflammation. FcγRI plays a critical role in antibody-based immunotherapy, which has important implications for the development of therapeutic drugs and methods for a variety of autoimmune diseases, infectious diseases, and tumors [4-5].
This model represents a humanized FCGR1 mouse, generated by substituting the mouse Fcgr1 gene sequence (inclusive of the UTR) with the corresponding human FCGR1 gene sequence. This modification enables the expression of human FcγRI in mice. Homozygous B6-hFCGR1 mice exclusively express human FcγRI receptors, with the proportion of cells expressing human FcγRI mirroring that of cells expressing mouse FcγRI in wild-type mice. Consequently, this model serves as a valuable tool for various research areas, including the evaluation of human IgG antibody affinity, exploration of the ADCC mechanism, investigation into immune cell phagocytosis and antigen presentation. Furthermore, it provides a platform for the preclinical assessment of therapeutic human IgG antibodies.
FCGR1 gene encodes FcγRI, a specific receptor for IgG antibodies, also known as CD64. This receptor plays a key role in human immune responses. FcγRI has a high affinity for the Fc portion of IgG antibodies and is the only member of the human FcγRs with a high affinity for monomeric IgG. It plays important roles in both innate and adaptive immune responses [1]. FcγRI is expressed on a variety of immune cells, including monocytes, macrophages, dendritic cells, and neutrophils. It plays a critical role in host defense against infection and humoral immunity by influencing processes such as phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and antigen presentation [2-3]. The binding of FcγRI to IgG-coated target cells promotes their phagocytosis by immune cells. This is an important mechanism for clearing infected cells, apoptotic cells, and other foreign particles. In addition, this binding can also promote the release of cytotoxic granules by immune cells, such as natural killer cells and cytotoxic T cells, leading to the killing and lysis of target cells. In antigen presentation, FcγRI binding to IgG-coated antigens promotes dendritic cells to take them up and present them to T cells, which is essential for the initiation of adaptive immune responses. In addition, FcγRI is involved in a variety of important physiological processes, such as wound healing and inflammation. FcγRI plays a critical role in antibody-based immunotherapy, which has important implications for the development of therapeutic drugs and methods for a variety of autoimmune diseases, infectious diseases, and tumors [4-5].
This model represents a humanized FCGR1 mouse, generated by substituting the mouse Fcgr1 gene sequence (inclusive of the UTR) with the corresponding human FCGR1 gene sequence. This modification enables the expression of human FcγRI in mice. Homozygous B6-hFCGR1 mice exclusively express human FcγRI receptors, with the proportion of cells expressing human FcγRI mirroring that of cells expressing mouse FcγRI in wild-type mice. Consequently, this model serves as a valuable tool for various research areas, including the evaluation of human IgG antibody affinity, exploration of the ADCC mechanism, investigation into immune cell phagocytosis and antigen presentation. Furthermore, it provides a platform for the preclinical assessment of therapeutic human IgG antibodies.
B6-hINHBE/ob
Product ID:
C001600
Strain:
C57BL/6NCya;C57BL/6JCya
Status:
Description:
Inhibin βE subunit (INHBE) is a member of the transforming growth factor-β (TGF-β) superfamily, highly specifically expressed in liver cells. The precursor protein of INHBE generates the inhibin β subunit after proteolytic processing. This protein is associated with various cellular processes, including cell proliferation, apoptosis, immune response, and hormone secretion. During the development of obesity and diabetes, the expression of INHBE protein inhibits the proliferation and growth of relevant cells in the pancreas and liver. Research has found a positive correlation between INHBE expression in the liver and insulin resistance and body mass index (BMI), suggesting that INHBE may be a liver factor in altering systemic metabolic status under conditions of obesity-related insulin resistance [1]. The studies conducted by Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC), respectively, revealed the close relationship between INHBE and fat regulation. The research demonstrated that rare loss-of-function variants in INHBE may protect the liver from the impact of inflammation, abnormal blood lipids, and type 2 diabetes by promoting healthy fat storage. Patients carrying such mutations exhibit more normal fat distribution, significantly reduced abdominal fat, improved metabolic conditions, and a decreased risk of cardiovascular diseases and type 2 diabetes [2-4]. These findings suggest that INHBE is a liver-specific negative regulator of fat storage. Inhibiting the expression of INHBE genes and proteins may be a potential strategy for treating metabolic disorders related to improper fat distribution and storage. Consequently, several small nucleic acid pharmaceutical companies, including Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, and Wave Life Sciences, are currently developing RNA interference (RNAi) drugs targeting INHBE to treat obesity [5-7].
The leptin (LEP) gene, also known as the OB gene, encodes the leptin protein, which is secreted into the circulation by white adipocytes and plays a major role in regulating energy homeostasis. Circulating leptin binds to leptin receptors (LEPR) in the brain, activating downstream signaling pathways that inhibit feeding and promote energy expenditure. Leptin also has multiple endocrine functions and is involved in physiopathological processes such as immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation, and wound healing [8]. Mutations in the LEP gene and its regulatory regions lead to severe obesity and morbid obesity with hypogonadism in humans and are also associated with the development of type II diabetes [9].
The B6-hINHBE/ob mouse model, generated by mating B6-hINHBE mice (Catalog Number: C001533) with Lep KO (ob/ob) mice (Catalog Number: C001368), is a metabolic disease model. It can be used for research on obesity, type II diabetes, and metabolic diseases related to improper fat distribution and storage, and for the development of human INHBE-targeted therapies.
Inhibin βE subunit (INHBE) is a member of the transforming growth factor-β (TGF-β) superfamily, highly specifically expressed in liver cells. The precursor protein of INHBE generates the inhibin β subunit after proteolytic processing. This protein is associated with various cellular processes, including cell proliferation, apoptosis, immune response, and hormone secretion. During the development of obesity and diabetes, the expression of INHBE protein inhibits the proliferation and growth of relevant cells in the pancreas and liver. Research has found a positive correlation between INHBE expression in the liver and insulin resistance and body mass index (BMI), suggesting that INHBE may be a liver factor in altering systemic metabolic status under conditions of obesity-related insulin resistance [1]. The studies conducted by Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC), respectively, revealed the close relationship between INHBE and fat regulation. The research demonstrated that rare loss-of-function variants in INHBE may protect the liver from the impact of inflammation, abnormal blood lipids, and type 2 diabetes by promoting healthy fat storage. Patients carrying such mutations exhibit more normal fat distribution, significantly reduced abdominal fat, improved metabolic conditions, and a decreased risk of cardiovascular diseases and type 2 diabetes [2-4]. These findings suggest that INHBE is a liver-specific negative regulator of fat storage. Inhibiting the expression of INHBE genes and proteins may be a potential strategy for treating metabolic disorders related to improper fat distribution and storage. Consequently, several small nucleic acid pharmaceutical companies, including Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, and Wave Life Sciences, are currently developing RNA interference (RNAi) drugs targeting INHBE to treat obesity [5-7].
The leptin (LEP) gene, also known as the OB gene, encodes the leptin protein, which is secreted into the circulation by white adipocytes and plays a major role in regulating energy homeostasis. Circulating leptin binds to leptin receptors (LEPR) in the brain, activating downstream signaling pathways that inhibit feeding and promote energy expenditure. Leptin also has multiple endocrine functions and is involved in physiopathological processes such as immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation, and wound healing [8]. Mutations in the LEP gene and its regulatory regions lead to severe obesity and morbid obesity with hypogonadism in humans and are also associated with the development of type II diabetes [9].
The B6-hINHBE/ob mouse model, generated by mating B6-hINHBE mice (Catalog Number: C001533) with Lep KO (ob/ob) mice (Catalog Number: C001368), is a metabolic disease model. It can be used for research on obesity, type II diabetes, and metabolic diseases related to improper fat distribution and storage, and for the development of human INHBE-targeted therapies.
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