The ABCD1 (ATP-binding cassette subfamily D member 1) gene, located on the X chromosome (Xq28), encodes a peroxisomal transmembrane protein responsible for transporting very long-chain fatty acids (VLCFAs) into peroxisomes for β-oxidation. Widely expressed but particularly prominent in the brain, adrenal glands, and liver, ABCD1 is critical for maintaining lipid homeostasis. Mutations in ABCD1 cause X-linked adrenoleukodystrophy (X-ALD), a neurodegenerative disorder characterized by VLCFA accumulation, demyelination, adrenal insufficiency, and progressive neurological decline. Clinical manifestations vary widely, ranging from asymptomatic carriers to a severe, fatal childhood form. Primarily affecting males (with an estimated incidence of ~1 in 17,000 newborns), X-ALD has been included in newborn screening programs in many U.S. states ^[1-2]. The correlation between specific mutations and symptoms remains unclear, and VLCFA measurement cannot reliably predict disease-specific outcomes such as adrenal insufficiency or neurological decline. Current therapeutic approaches focus on gene repair or mitigating secondary effects like oxidative stress ^[3]. The Abcd1 KO mouse, a gene knockout model generated by deleting exon 2 of the mouse Abcd1 gene (homologous to human ABCD1), serves as a valuable tool for studying the pathogenesis of X-ALD and developing therapeutic interventions.

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]. As a target for antibody-mediated cancer therapy, TFR1 can be leveraged through two approaches: one involves the use of antibodies conjugated to anti-cancer drugs, which are indirectly internalized via receptor-mediated endocytosis; the other employs antibodies that directly disrupt receptor function or induce Fc effector functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). 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). The B6-hTFRC (CDS) mouse model was generated by inserting the human TFRC gene sequence into the mouse Tfrc gene locus using gene-editing technology. To minimize interference from mouse gene sequences or proteins, part of the mouse Tfrc gene sequence was knocked out, resulting in a model expressing only the human TFR1 protein. This model is valuable for studying iron metabolism disorders, neurodegenerative diseases, and tumor development, supporting the development of TFR1-targeted therapeutics and preclinical pharmacological evaluations.

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.

Calcitonin-related polypeptide alpha (CALCA) is a protein-encoded gene, also known as CALC1, CGRP, or CGRP-α. Multiple genetic factors and epigenetic modifications regulate CALCA gene expression, and it forms peptide hormones calcitonin (CT), α-isoform of calcitonin gene-related peptide (CGRP), and katacalcin through tissue-specific RNA alternative splicing and non-active precursor protein cleavage in transcription and translation. Calcitonin is synthesized and secreted by thyroid parafollicular cells, mainly involved in regulating calcium levels and phosphorus metabolism in bones and kidneys. It can reduce the concentration of calcium and phosphorus in the plasma and inhibit the absorption of calcium and phosphorus. CGRP mainly acts as a vasodilator and antimicrobial peptide, which can cause dilatation of coronary arteries, cerebral vessels, and systemic vessels, and help to regulate blood pressure. CGRP is also widely distributed in the pain pathways of the peripheral and central nervous system (CNS) of the human body, and its receptors are also expressed in the pain pathways. CGRP participates in the transmission of pain signals from the periphery to the CNS and plays a key role in pain regulation, which is related to the pathogenesis of a variety of pain diseases and related syndromes, including somatic pain, visceral pain, neuropathic pain, inflammatory pain, and migraine. Katacalcin mainly exists as a peptide that can effectively lower plasma calcium, and its effect of lowering serum calcium levels is almost the same as that of calcitonin. CALCA gene polymorphism is associated with a variety of diseases, including reflex sympathetic dystrophy syndrome, complex regional pain syndrome, ischemic stroke, Parkinson's disease, ovarian cancer, bone mineral density, migraine, schizophrenia, bipolar disorder, and primary hypertension ^[1-5]. CALCA is a potential target for new therapies for a variety of diseases. Currently, various CALCA antagonists are being developed for the treatment of migraine and primary hypertension, and research on targeting CALCA for diseases such as Alzheimer's disease and Parkinson's disease is also ongoing ^[6-7]. This strain is a humanized mouse model of the Calca gene. Using gene editing technology, the base sequence of the mouse Calca gene from the start codon to the 3’UTR region was replaced by the corresponding sequence in the human CALCA gene, while the 5’UTR region of the mouse Calca gene was retained. Homozygous B6-hCALCA mice are viable and fertile and can be used to study the mechanisms of various physiological and pathological processes such as blood pressure regulation, cell proliferation, cell apoptosis, vascular biology, physiological bone marrow production, inflammation, tumor growth, and research on CALCA-targeted migraine drugs and therapies.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), also known as cluster of differentiation 152 (CD152), is an immunoglobulin superfamily protein encoded by the CTLA4 gene. CTLA4 is expressed by activated T cells and delivers inhibitory signals to T cells ^[1]. The structure of the CTLA4 protein contains a V-domain, a transmembrane domain, and a cytoplasmic tail. Different splicing patterns of CTLA4 pre-mRNA lead to the appearance of different isoforms, among which the membrane-bound isoform is linked by disulfide bonds to form homodimers, while the soluble isoform exists as a monomer. CTLA4 is homologous to CD28, which delivers T-cell activation signals. Both molecules compete for binding to the natural B7 family ligands B7-1 and B7-2 on antigen-presenting cells, but CTLA4 has a much higher affinity for binding to B7-1 and B7-2 than CD28. This results in the inhibition of T cell activation, allowing tumor cells to escape from T cell attack ^[2]. The gene is closely associated with the occurrence or progression of insulin-dependent diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated ophthalmopathy, and other autoimmune diseases ^[3]. CTLA4 is a membrane protein, with its extracellular domain serving as the receptor/ligand binding region and its intracellular domain responsible for signal transduction ^[4]. This strain was generated by gene editing to replace the extracellular domain of Ctla4 in mice with the humanized version, resulting in a model that expresses the extracellular domain of human CTLA4 and the intracellular domain of mouse CTLA4. This model can be used for the research of the development and screening of CTLA4-related inhibitors or antibody drugs, the evaluation of pharmacodynamics and safety, the evaluation of tumor immunotherapy, and the mechanisms of the immune system.

Spinocerebellar ataxias (SCAs) are a group of genetic diseases that mainly manifest as chronic progressive ataxia, such as limping, sudden falls, and difficulty in pronunciation. The main lesion sites of these diseases are the cerebellum and its associated tissues. They are mostly inherited in an autosomal dominant manner, but there are also autosomal recessive and X-linked inheritance types. The average incidence of SCA is 2.7 per 100,000 people ^[1]. SCA can be divided into repeat expansion type and non-repeat expansion type according to the genetic mutation type. Among them, repeat expansion type includes polyglutamine SCA and non-translated region repeat expansion type SCA. Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), belongs to polyglutamine SCA and is the most common dominant hereditary ataxia. The pathogenesis of SCA3 is the loss of neurotransmitters caused by CAG repeat expansion in the ATXN3 gene. This expansion results in a long polyglutamine (polyQ) domain in the Ataxin 3 protein, leading to protein aggregation and dysfunction of the ubiquitin-proteasome system. The CAG repeat number in the healthy human ATXN3 gene ranges from 12 to 44, while the polyQ domain of SCA3 patients abnormally increases, with CAG repeat numbers ranging from 56 to 87. Individuals with CAG repeat numbers between 45 and 55 exhibit incomplete penetrance of SCA3 symptoms. Like other PolyQ diseases, the CAG repeat number is negatively correlated with the age of onset of SCA3 and positively correlated with the severity of the disease ^[2-3]. Currently, most SCA treatments targeting the ATXN3 gene are in the early stages of development and mainly involve reducing abnormal ATXN3 expression through means such as miRNA or ASO drugs. The Ataxin 3 protein in mice does not contain or only contains a shorter polyQ structure. Considering the differences between humans and mice in terms of genes, humanizing mouse genes can help accelerate these treatments into clinical stages. This strain is a mouse Atxn3 gene humanized model that can be used for research on Spinocerebellar ataxia type 3 (SCA3) ^[4-9]. The homozygous B6-hATXN3 mice are viable and fertile. 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.

Familial dysautonomia (FD) is a rare autosomal recessive genetic neurological disorder. Patients with FD exhibit symptoms such as excessive sweating, intermittent hypertension, drooling, abnormal glandular secretion, difficulty swallowing, urinary and fecal incontinence, breathing difficulties, periodic vomiting, and physical developmental abnormalities, including intellectual disability and osteoporosis. FD primarily results from underdeveloped cervical sympathetic ganglia, with mutations in the ELP1 gene being a significant genetic factor. The ELP1 gene, also known as IKBKAP, encodes components of the elongation complex essential for tRNA modification. This widely expressed protein plays a crucial role in neuronal development and function. Mutations in both copies of the ELP1 gene can lead to decreased or absent ELP1 protein levels, causing neuronal damage and potentially contributing to FD symptoms^[1]. There is no mature cure for FD. Treatment primarily focuses on symptomatic relief and supportive care to alleviate symptoms and prevent complications. Gene therapy, a promising approach, targets the underlying cause of FD---gene mutations---enhancing treatment efficiency and persistence. This field is expected to be the next breakthrough. At present, the ELP1 targeted drug pipeline has begun to be laid out. The preclinical animal models are mostly transgenic humanized mice. Compared with randomly inserted, humanized region-restricted transgenic humanized mice, more scientific and efficient whole-genome humanized animal models will help promote the potential therapy targeting ELP1 to accelerate into the clinical stage. This strain is a mouse Elp1 gene humanized model and can be used to research Familial dysautonomia (FD). The homozygous B6-hELP1 mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation (ELP1 IVS20+6T>C) models based on this strain and provide customized services for specific mutations.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the progressive loss of anterior horn motor neurons in the spinal cord, leading to muscle weakness and atrophy. This can affect the muscles that control breathing, crawling, walking, head and neck control, and swallowing, increasing the risk of pneumonia and respiratory infections in patients. SMA is the most common fatal neurogenetic disease in infancy, with an incidence rate of 1/6,000 to 1/10,000. SMA is caused by mutations in the SMN1 gene, which encodes a protein essential for motor neuron survival. The human genome also contains the SMN2 gene, which is highly homologous to SMN1 but differs in splicing patterns. A c.840C>T mutation in the splicing enhancer of exon 7 of SMN2 causes it to produce mostly truncated mRNA, which encodes a non-functional protein. Only a small portion of SMN2 mRNA, approximately 10%~15%, is spliced into full-length mRNA, which encodes functional protein ^[1]. Approximately 95% of SMA patients carry either the homozygous SMN1 exon 7 deletion mutation or the homozygous mutation that converts SMN1 to SMN2, and the inability of SMN2 expression to compensate for the deletion of SMN proteins leads to disease ^[2]. Mice are the most common preclinical experimental subjects for SMA, but they only have the Smn1 gene, and the deletion of both Smn1 alleles leads to lethality. Therefore, it is crucial to develop mouse models that can simulate human SMA pathogenesis and progression. Current therapies for SMA aim to supplement SMN1 genes or selectively regulate SMN2 splicing. Targeted therapy for SMN2 changes its splicing pattern to increase the expression of full-length SMN protein ^[3]. The application of fully humanized animal models can help promote the further translation of potential SMA-related therapies into clinical trials. This strain is a humanized SMN2 gene model of spinal muscular atrophy (SMA). The endogenous Smn1 gene in mice was replaced with the human SMN2 gene fragment to simulate the pathogenesis of SMA patients in mice. However, since the SMN2 gene mainly produces the SMNΔ7 protein, which lacks exon 7, the humanized SMN2 gene cannot fully compensate for the abnormalities caused by the loss of the Smn1 gene, resulting in an SMA-like phenotype in the model. Due to the correlation between SMA subtypes and SMN2 copy numbers, this model can be mated with Rosa26-hSMN2 mice, which have SMN2 genes inserted in chromosome 6, to increase the copy number of SMN2 in mice and improve the survival period of the model. This can simulate different SMA subtypes, which can be used for more relevant pathogenic mechanisms and preclinical studies of drugs.

Apolipoprotein E (APOE) is a critical apolipoprotein involved in lipid transport mediated by lipoproteins. As a core component of plasma lipoproteins, APOE facilitates the transport of lipids through plasma and interstitial fluid between organs, and it plays a pivotal role in the generation, conversion, and clearance of lipoproteins. In humans, the APOE gene has three isoforms (E2, E3, E4) associated with atherosclerosis and Alzheimer’s disease (AD), with the E4 allele present in approximately 14% of the population ^[1]. The ApoE4 isoform is a major genetic risk factor for late-onset Alzheimer’s disease (AD), exacerbating neurodegeneration. ApoE4-associated damage to vascular systems in the brain could have a key role in AD pathogenesis ^[2]. Beyond AD, APOE4 is linked to cardiovascular diseases due to its influence on lipid homeostasis ^[3]. The tau protein, a microtubule-associated protein encoded by MAPT is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. By binding to microtubules, the tau protein helps to maintain neuronal cell shape. Mutations in MAPT can promote tau aggregation, leading to pathological tau protein accumulation and death of glutamatergic cortical neurons ^[4]. Additionally, certain MAPT mutations can affect pre-mRNA exon splicing, altering the ratio of 3R to 4R tau protein isoforms and increasing the relative production of 4R-tau protein, which is more prone to fibril formation ^[5]. Therapies targeting the MAPT gene primarily consist of small molecule drugs and monoclonal antibodies, with indications including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). MAPT is the earliest discovered and most frequently implicated in FTD. Mutations in the MAPT gene are detectable in roughly 30% of familial FTD cases ^[6]. The B6-APOE4/htau mouse is a model generated by crossing B6-APOE4 mice (Catalog No.: C001079) with B6-htau mice (Catalog No.: C001410). It can be used to study the pathogenic mechanisms and therapeutic approaches of neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and cerebral amyloid angiopathy (CAA), as well as cardiovascular diseases such as atherosclerosis.

Apolipoprotein E (APOE) is a critical apolipoprotein involved in lipid transport mediated by lipoproteins. As a core component of plasma lipoproteins, APOE facilitates the transport of lipids through plasma and interstitial fluid between organs, and it plays a pivotal role in the generation, conversion, and clearance of lipoproteins. In humans, the APOE gene has three isoforms (E2, E3, E4) associated with atherosclerosis and Alzheimer’s disease (AD), with the E4 allele present in approximately 14% of the population ^[1]. The ApoE4 isoform is a major genetic risk factor for late-onset Alzheimer’s disease (AD), exacerbating neurodegeneration. ApoE4-associated damage to vascular systems in the brain could have a key role in AD pathogenesis ^[2]. Beyond AD, APOE4 is linked to cardiovascular diseases due to its influence on lipid homeostasis ^[3]. The tau protein, a microtubule-associated protein encoded by MAPT is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. By binding to microtubules, the tau protein helps to maintain neuronal cell shape. Mutations in MAPT can promote tau aggregation, leading to pathological tau protein accumulation and death of glutamatergic cortical neurons ^[4]. Additionally, certain MAPT mutations can affect pre-mRNA exon splicing, altering the ratio of 3R to 4R tau protein isoforms and increasing the relative production of 4R-tau protein, which is more prone to fibril formation. Common mutations include P301L, P301S, and Intron10+3 G>A ^[5]. The P301L mutation affects the 4R-tau isoforms without affecting splicing in exon 10. This mutation accelerates the formation of paired helical filaments in tau proteins, reduces microtubule interactions and stability, and promotes β-sheet folding during the aggregation process. This leads to abnormal tau protein aggregation, resulting in neurofibrillary tangles—a characteristic feature of neurodegenerative diseases ^[6-7]. Therapies targeting the MAPT gene primarily consist of small molecule drugs and monoclonal antibodies, with indications including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). MAPT is the earliest discovered and most frequently implicated in FTD. Mutations in the MAPT gene are detectable in roughly 30% of familial FTD cases ^[8]. The B6-APOE4/htau*P301L mouse is a model generated by crossing B6-APOE4 mice with B6-htau*P301L mice. It can be used to study the pathogenic mechanisms and therapeutic approaches of neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and cerebral amyloid angiopathy (CAA), as well as cardiovascular diseases such as atherosclerosis.