The ALPL gene encodes for the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, a membrane-bound glycoprotein. This enzyme is expressed in a variety of cellular tissues, most notably in the liver, bone, and kidney, as well as in other areas like teeth and mesenchymal stem cells ^[1]. Its primary function is to act as a hydrolase, removing phosphate groups from molecules. This is a critical function for skeletal and dental mineralization, where it hydrolyzes inorganic pyrophosphate (a mineralization inhibitor) into phosphate, which then combines with calcium to form bone ^[2]. Mutations in the ALPL gene lead to hypophosphatasia (HPP), a rare inherited metabolic disease characterized by defective bone and tooth mineralization, rickets, osteomalacia, and in severe cases, seizures and respiratory complications. The severity of HPP varies, ranging from mild forms with dental issues to life-threatening perinatal forms ^[3]. Variations in the ALPL gene may also be associated with other diseases, such as osteoporosis. Research has found a high frequency of homozygous common ALPL gene variants in adult patients with atypical femoral fractures or with biochemical/clinical signs of hypophosphatasia (HPP). This suggests that variations in the ALPL gene may be linked to an increased risk of these fractures ^[4]. Furthermore, the expression and function of the ALPL gene may be relevant to cancer immunotherapy. Studies have shown that an alkaline phosphatase isoform, known as ALPL-1, is highly expressed in osteosarcoma (OS) ^[5]. The Alpl KO mouse is a knockout (KO) model in which the exon 3~4 of the Alpl gene (homologous to the human ALPL gene) has been deleted via gene-editing technology. Preliminary validation data indicate that homozygous Alpl KO mice have a short lifespan, dying within four weeks when given a specialized diet. If they are not provided with this dietary support, no surviving homozygous individuals are obtained. This model can be used to study the pathogenic mechanisms of diseases such as hypophosphatasia (HPP), osteoporosis, and osteosarcoma (OS), and to provide a basis for developing related therapeutic strategies.

Stargardt disease (STGD), a hereditary macular dystrophy, is characterized by the presence of yellowish flecks within the retinal pigment epithelium (RPE), ultimately culminating in macular atrophy. Typically manifesting in childhood and adolescence, STGD leads to progressive central vision loss and mild dyschromatopsia. Fundoscopic examination may reveal pale yellow lesions exhibiting a characteristic gold foil-like sheen, accompanied by yellow-white spots surrounding the posterior pole. In advanced stages, atrophy of the RPE, photoreceptors, and choriocapillaris is observed. This bilateral and typically synchronous condition affects both eyes with comparable incidence across sexes, estimated between 1/8,000 and 1/13,000. STGD is predominantly an autosomal recessive disorder, with mutations in the ABCA4 gene accounting for approximately 95% of cases. ABCA4 encodes a retina-specific ABC transporter protein crucial for the clearance of retinal derivatives and toxic metabolites generated during rhodopsin photobleaching. Consequently, ABCA4 mutations result in the accumulation of these cytotoxic substances, triggering apoptosis of both RPE and photoreceptor cells and ultimately driving retinal degeneration. Notably, ABCA4 mutations have been implicated in a spectrum of retinal diseases, including STGD, cone-rod dystrophy (CRD), age-related macular degeneration (AMD), and retinitis pigmentosa (RP), with the specific clinical phenotype correlating with the nature and severity of the ABCA4 mutation. This strain is an Abca4 gene knockout (KO) mouse model. Gene-editing technology was used to delete the protein-coding sequence of the Abca4 gene (the homolog of the human ABCA4 gene) in mice. Previous studies have demonstrated that Abca4 KO mice exhibit delayed dark adaptation following photobleaching and a slow progression of photoreceptor degeneration^[1]. Homozygous Abca4 KO mice are viable and fertile.

The AGXT gene, mapping to chromosome 2q37.3, encodes alanine-glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate-dependent homotetrameric enzyme predominantly expressed in hepatic peroxisomes ^[1]. AGT is central to glyoxylate metabolism, catalyzing its transamination to glycine and preventing its oxidation to oxalate ^[1]. Primary Hyperoxaluria Type 1 (PH1), a rare autosomal recessive disorder affecting approximately 1-3 per million individuals, arises from over 175 identified pathogenic mutations in AGXT. These mutations typically result in deficient or mislocalized AGT, leading to marked overproduction of oxalate ^[2]. The ensuing hyperoxaluria causes deposition of calcium oxalate in the kidneys, manifesting as nephrolithiasis and nephrocalcinosis, which can progress to end-stage renal disease ^[3]. In severe cases, systemic oxalosis can occur ^[4]. Agxt-deficient mice serve as critical preclinical models, faithfully mirroring the biochemical and pathological features of PH1 and enabling the evaluation of diverse therapeutic modalities, including enzyme replacement, substrate reduction, and gene therapy. The Agxt KO mouse is a gene knockout model created using gene-editing techniques to knock out the coding sequence of the Agxt gene (the homolog of the human AGXT gene) in mice. This model is used to research the pathogenic mechanisms of primary hyperoxaluria and develop related therapeutic strategies.

The ATP7B gene encodes a copper-transporting ATPase β-peptide that is a member of the P-type cation-transporting ATPase family, which uses the energy stored in adenosine triphosphate (ATP) molecules to transport metals into and out of cells. The ATP7B protein consists of multiple transmembrane structural domains, an ATPase consensus sequence, a hinge structural domain, and a phosphorylation site, as well as at least two putative copper-binding sites ^[1]. This protein is found mainly in the liver and to a lesser extent in the kidney and brain, and functions as a copper-transporting ATPase that plays a role in transporting copper from the liver to other parts of the body. Copper is an important component of certain enzymes that maintain normal cellular function, and the ATP7B protein is important for the removal of excess copper from the body. Mutations in this gene are associated with Wilson disease (WD), which is characterized by the accumulation of copper to toxic levels that damage tissues and organs such as the liver and brain as the removal of excess copper from the body is compromised with the absence of the functional ATP7B protein ^[2-4]. This strain is an Atp7b deletion mouse model, which uses gene editing technology to knock out Atp7b, the homolog of the human ATP7B gene in mice that lack the expression of ATP7B protein and can be used in the study of disorders related to copper metabolisms such as Wilson's disease, acute liver failure, and steatohepatitis. The heterozygous Atp7b KO mice are viable and fertile, and homozygous mice have a reduced life expectancy.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a critical protein that maintains the salt and water balance across various human organs, including the lungs, pancreas, and sweat glands. The primary function of CFTR is to act as a chloride channel, regulating the transport of chloride and bicarbonate ions across epithelial cell membranes, thereby maintaining tissue fluid balance and pH. This process is ATP-dependent and also modulates the activity of other ion channels and transport proteins ^[1-2]. Mutations in the CFTR gene can lead to chloride channel dysfunction, resulting in various diseases, with cystic fibrosis (CF) being the most common. CF is the most prevalent lethal genetic disease among Caucasians, with an incidence of approximately 1/2,500 to 1/1,800, and about 90,000 cases globally ^[3-4]. The disease is characterized by thickened mucus in the lungs, frequent respiratory infections, pancreatic insufficiency, and male infertility, typically due to vas deferens obstruction. The W1282X mutation is a prevalent and severe class I nonsense mutation (c.3846G>A, p.Trp1282Ter) in the CFTR gene, notably common in the Ashkenazi Jewish population ^[5]. This genetic alteration introduces a premature termination codon at position 1282, which prematurely truncates the synthesis of the CFTR protein. Consequently, the resulting shortened polypeptide is unstable and the corresponding mRNA is often degraded via the nonsense-mediated mRNA decay (NMD) pathway, leading to a near-complete absence of functional CFTR protein and an associated severe clinical phenotype of Cystic Fibrosis (CF). Current treatments for CF mainly focus on CFTR modulators to restore the function of the mutated CFTR protein. CFTR modulators are classified into potentiators (which enhance CFTR function) and correctors (which assist in the proper folding and trafficking of CFTR to the cell membrane). Representative drugs include Ivacaftor, Lumacaftor, and triple-combination CFTR modulating therapy Elexacaftor-Tezacaftor-Ivacaftor ^[6]. B6-huCFTR*W1282X mice were developed by introducing the W1282X mutation into the CFTR-humanized mouse model (Catalog Number: I001132), creating a humanized disease model. It is suitable for research into CF mechanisms and the development of therapies targeting the CFTR W1282X mutation. This strain requires feeding with intestinal cleansers to maintain survival. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on the CFTR-humanized strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a critical protein that maintains the salt and water balance across various human organs, including the lungs, pancreas, and sweat glands. The primary function of CFTR is to act as a chloride channel, regulating the transport of chloride and bicarbonate ions across epithelial cell membranes, thereby maintaining tissue fluid balance and pH. This process is ATP-dependent and also modulates the activity of other ion channels and transport proteins ^[1-2]. Mutations in the CFTR gene can lead to chloride channel dysfunction, resulting in various diseases, with cystic fibrosis (CF) being the most common. CF is the most prevalent lethal genetic disease among Caucasians, with an incidence of approximately 1/2,500 to 1/1,800, and about 90,000 cases globally ^[3-4]. The disease is characterized by thickened mucus in the lungs, frequent respiratory infections, pancreatic insufficiency, and male infertility, typically due to vas deferens obstruction. The G551D mutation is a clinically significant genetic defect in the CFTR gene, which is classified as a Class III mutation and is the third most common CF-associated mutation worldwide, occurring in about 3% of CF patients ^[5]. This missense mutation involves a single amino acid substitution where Glycine (G) is replaced by Aspartic Acid (D) at position 551 within the first Nucleotide Binding Domain (NBD1) of the CFTR protein. The defining molecular pathology is a severe gating defect; while the CFTR chloride channel is correctly processed and successfully trafficked to the apical membrane of epithelial cells, its probability of opening is drastically reduced (approximately 100-fold lower than the wild-type channel). This impairment in channel opening results in a critical reduction in chloride and bicarbonate transport, leading to the characteristic buildup of thick, dehydrated mucus in multiple organs and a severe clinical phenotype. Current treatments for CF mainly focus on CFTR modulators to restore the function of the mutated CFTR protein. CFTR modulators are classified into potentiators (which enhance CFTR function) and correctors (which assist in the proper folding and trafficking of CFTR to the cell membrane). Representative drugs include Ivacaftor, Lumacaftor, and triple-combination CFTR modulating therapy Elexacaftor-Tezacaftor-Ivacaftor ^[6]. The G551D mutation holds particular importance in CF research and therapy as it was the first genotype-specific mutation to be successfully targeted by a CFTR potentiator drug, Ivacaftor, which functions by increasing the opening probability of the mutant channel. B6-huCFTR*G551D mice were developed by introducing the G551D mutation into the CFTR-humanized mouse model (Catalog Number: I001132), creating a humanized disease model. It is suitable for research into CF mechanisms and the development of therapies targeting the CFTR G551D mutation. This strain requires feeding with intestinal cleansers to maintain survival. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on the CFTR-humanized strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a critical protein that maintains the salt and water balance across various human organs, including the lungs, pancreas, and sweat glands. The primary function of CFTR is to act as a chloride channel, regulating the transport of chloride and bicarbonate ions across epithelial cell membranes, thereby maintaining tissue fluid balance and pH. This process is ATP-dependent and also modulates the activity of other ion channels and transport proteins ^[1-2]. Mutations in the CFTR gene can lead to chloride channel dysfunction, resulting in various diseases, with Cystic Fibrosis (CF) being the most common. CF is the most prevalent lethal genetic disease among Caucasians, with an incidence of approximately 1/2,500 to 1/1,800, and about 90,000 cases globally ^[3-4]. The disease is characterized by thickened mucus in the lungs, frequent respiratory infections, pancreatic insufficiency, and male infertility, typically due to vas deferens obstruction. The F508del and G542X are the most common mutations found in US patients, accounting for 86.4% and 4.6% of all mutations, respectively ^[5]. The G542X mutation is a common and severe cause of Cystic Fibrosis (CF), resulting from a single point mutation in the CFTR gene that creates a premature termination codon (PTC) at amino acid position 542; this classifies G542X as a Class I nonsense mutation. The presence of this PTC triggers a cellular quality control mechanism known as Nonsense-Mediated Decay (NMD), which targets the mutant mRNA for degradation, leading to a near-complete absence of functional CFTR protein at the epithelial cell surface. Consequently, patients with two copies of G542X often exhibit a severe form of CF, characterized by major organ dysfunction, and this lack of protein makes it a primary target for novel therapeutic strategies, such as readthrough agents and gene editing. Current treatments for CF mainly focus on CFTR modulators to restore the function of the mutated CFTR protein. CFTR modulators are classified into potentiators (which enhance CFTR function) and correctors (which assist in the proper folding and trafficking of CFTR to the cell membrane). Representative drugs include Ivacaftor, Lumacaftor, and triple-combination CFTR modulating therapy Elexacaftor-Tezacaftor-Ivacaftor ^[6]. B6-huCFTR*G542X mice were developed by introducing the G542X mutation into the CFTR-humanized mouse model (Catalog Number: I001132), creating a humanized disease model. It is suitable for research into CF mechanisms and the development of therapies targeting the CFTR G542X mutation. This strain requires feeding with intestinal cleansers to maintain survival. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on the CFTR-humanized strain and provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields.

Marfan syndrome (MFS) is an autosomal dominant systemic connective tissue disorder with a prevalence of 1/3,000–1/5,000, unaffected by race or geographic location. Patients typically exhibit disproportionately long limbs, fingers, and toes, and significantly exceed average height. Clinically, the disease presents with diverse manifestations, with the most life-threatening complications involving the cardiovascular system, including mitral valve prolapse, aortic valve regurgitation, aortic root dilation, and aortic dissection. This connective tissue disorder affects multiple organ systems, including the skeletal, pulmonary, ocular, central nervous, and cardiovascular systems ^[1]. The FBN1 gene is the causative gene for MFS, which encodes fibrillin-1, a connective tissue protein that provides structural support to cells as an extracellular matrix component and imparts elasticity and strength to connective tissues. FBN1 mutations can lead to a spectrum of type I fibrillinopathies, including Marfan syndrome (MFS), dominant Weill-Marchesani syndrome, and scleroderma. Current therapeutic strategies for MFS primarily focus on preventive and symptomatic treatments, while gene therapy, potentially addressing both prevention and symptom management, shows promise as the next frontier in research. Studies have demonstrated that gene editing technologies can correct mutations in patient-derived induced pluripotent stem cells (iPSCs), marking a critical first step toward developing efficient and precise gene therapies for MFS ^[2-3]. Subsequent in vivo animal studies are indispensable for preclinical research. As gene therapies act on the human FBN1 gene, the development of fully humanized animal models is scientifically robust and adaptable to diverse drug targeting sites, accelerating the FBN1-targeted therapeutic approaches into clinical trials. The B6-hFBN1 mouse is a humanized model, generated by in situ replacement of the mouse Fbn1 gene sequence (including 3'UTR) with the corresponding human FBN1 sequence while retaining the mouse signal peptide. This model is suitable for research on the pathogenesis and therapeutic agents for Marfan syndrome (MFS), dominant Weill-Marchesani syndrome, scleroderma, and other related disorders. Additionally, leveraging its proprietary TurboKnockout fusion BAC recombination technology, Cyagen can provide popular mutation disease models based on this platform or offer customized services for different mutations to meet the experimental needs of researchers.

The ALB gene encodes albumin, mainly produced in the liver, and is the most abundant protein in human plasma, accounting for 60% to 65% of total plasma protein. The proprotein encoded by ALB is processed to produce a functional protein, and the EPI-X4 peptide derived from this protein is an endogenous inhibitor of the CXCR4 chemokine receptor. Albumin plays a role in regulating plasma colloid osmotic pressure, helping to maintain blood circulation and isolating and transporting many metabolites within the body, especially insoluble hydrophobic metabolites ^[1]. Human Serum Albumin (HSA) is an important carrier protein involved in the transport of a variety of endogenous molecules, including hormones, fatty acids, and metabolic products, as well as exogenous drugs. As a natural carrier protein, HSA has multiple ligand binding sites and a plasma half-life of up to 19 days, making it a promising drug carrier. Several HSA-based drug delivery systems have been approved for clinical trials ^[2-3]. In addition, albumin is also the main transporter of zinc, calcium, and magnesium in plasma, binding approximately 80% of all plasma zinc and approximately 45% of circulating calcium and magnesium, with an affinity ranking of zinc > calcium > magnesium ^[4]. Diseases associated with the ALB gene include hyperthyroxinemia, familial serum albumin abnormality, and analbuminemia ^[5]. The ALPL gene encodes for the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, a membrane-bound glycoprotein. This enzyme is expressed in a variety of cellular tissues, most notably in the liver, bone, and kidney, as well as in other areas like teeth and mesenchymal stem cells ^[6]. Its primary function is to act as a hydrolase, removing phosphate groups from molecules. This is a critical function for skeletal and dental mineralization, where it hydrolyzes inorganic pyrophosphate (a mineralization inhibitor) into phosphate, which then combines with calcium to form bone ^[7]. Mutations in the ALPL gene lead to hypophosphatasia (HPP), a rare inherited metabolic disease characterized by defective bone and tooth mineralization, rickets, osteomalacia, and in severe cases, seizures and respiratory complications. The severity of HPP varies, ranging from mild forms with dental issues to life-threatening perinatal forms ^[8]. Variations in the ALPL gene may also be associated with other diseases, such as osteoporosis. Research has found a high frequency of homozygous common ALPL gene variants in adult patients with atypical femoral fractures or with biochemical/clinical signs of hypophosphatasia (HPP). This suggests that variations in the ALPL gene may be linked to an increased risk of these fractures ^[9]. Furthermore, the expression and function of the ALPL gene may be relevant to cancer immunotherapy. Studies have shown that an alkaline phosphatase isoform, known as ALPL-1, is highly expressed in osteosarcoma (OS) ^[10]. B6-hALB/Alpl KO mice are generated by crossing B6-hALB (HSA) mice (Catalog No.: C001492) with Alpl KO mice (Catalog No.: C001849). Among them, Alpl KO mice are a gene knockout (KO) model: homozygous Alpl KO mice have a short lifespan, dying within 4 weeks even when fed with special feed; without special feed, no viable homozygous individuals can be obtained. This model can be used for research on the pathogenic mechanisms of diseases such as hypophosphatasia (HPP), osteoporosis, and osteosarcoma (OS), as well as for the development of therapeutic drugs using human serum albumin (HSA) as a carrier, and studies on in vivo efficacy and pharmacokinetics.

Epidermolysis bullosa (EB) is a hereditary skin disease characterized by the formation of blisters and bullae on the skin and mucous membranes after minor trauma or friction. Common clinical symptoms include blisters, blood blisters, and erosion on the skin. According to the different sites of onset, hereditary EB can be divided into three types: Epidermolysis Bullosa Simplex (EBS), Junctional Epidermolysis Bullosa (JEB), and Dystrophic Epidermolysis Bullosa (DEB). Mutations in the COL7A1 gene are the cause of Dystrophic Epidermolysis Bullosa (DEB), and the different clinical phenotypes presented by DEB are related to the mutation sites and forms of the COL7A1 gene. The COL7A1 gene encodes type VII collagen, which forms anchoring fibrils that bind dermal tissue to epidermal tissue. Functional anchoring fibril deficiency caused by COL7A1 mutations makes the patient’s skin extremely fragile and easily blistered or torn due to minor friction or trauma. At present, at least 324 pathogenic mutations of the COL7A1 gene related to DEB have been found, including nonsense, missense, deletion, insertion, splicing, and regulation ^[1]. The current DEB treatment pipeline is mainly based on gene therapy and small nucleic acid drugs, including ASO drugs, siRNA drugs, and gene therapy based on CRISPR and AAV vector delivery. Among them, COL7A1 is the most important therapeutic target. B-Vec, developed by Krystal Biotech delivers functional COL7A1 genes to skin cells of DEB patients with COL7A1 mutations through HSV-1 vectors to produce functional proteins to promote wound healing, was the first approved gene therapy drug for the DEB. In addition, since most ASO, siRNA, and CRISPR-based therapies target human COL7A1 genes, considering the genetic differences between animals and humans, humanizing mouse genes will help promote further clinical translation of therapies targeting COL7A1. This strain is a disease model constructed by introducing a common recurrent mutation (c.6527dupC) of the COL7A1 gene in human diseases into the mouse Col7a1 humanized model (Catalog Number: C001428) ^[2]。The homozygous B6-hCOL7A1*c.6527dupC mice exhibit a disease phenotype similar to human Dystrophic Epidermolysis Bullosa (DEB), and most mice die within 6 days after birth ^[3-7]. Leveraging its proprietary TurboKnockout fusion BAC recombination technology, Cyagen can also provide customized services for specific mutations to meet the experimental needs in pharmacology and other fields related to EB.