Duchenne Muscular Dystrophy (DMD) is a severe, progressive, and disabling X-linked recessive genetic disorder characterized primarily by muscle atrophy. This disease leads to motor impairments, eventually requiring assisted ventilation, and often results in premature death. The primary cause of DMD is mutations in the DMD gene, which encodes the dystrophin protein. These mutations lead to a reduction or absence of dystrophin in muscle tissue, resulting in muscle atrophy and related complications ^[1]. The lack of dystrophin leads to the breakdown of the dystrophin-associated protein complex (DAPC) within the muscle membrane, disrupting the interaction between actin and the extracellular matrix, making the muscles more susceptible to damage. This susceptibility results in the gradual loss of muscle tissue and function, potentially leading to cardiomyopathy ^[2]. Researchers have identified thousands of different DMD gene mutations in patients with DMD. Deletion mutations account for approximately 60%–70%, while duplication mutations account for 5%–15%. These mutations are primarily concentrated in hotspot regions of the DMD gene, specifically between exons 45-55 (47%) and exons 3-9 (7%) ^[1]. Currently, gene therapy approaches for Duchenne Muscular Dystrophy (DMD) primarily include exon skipping and AAV supplementation, as well as emerging gene editing techniques like CRISPR. The exon skipping strategy involves using antisense oligonucleotide (ASO) drugs to bind to specific sequences of pre-mRNA, skipping the mutated exon and restoring the open reading frame (ORF) integrity, thus producing a truncated but partially functional dystrophin protein. Several ASO drugs targeting the DMD gene have been approved, such as Eteplirsen (targeting exon 51), Golodirsen (targeting exon 53), and Casimersen (targeting exon 45) developed by Sarepta, and Viltolarsen (targeting exon 53) developed by Nippon Shinyaku. Since most ASO and CRISPR-based gene editing therapies target the human DMD gene, humanizing mouse genes helps accelerate clinical applications for DMD therapies, considering the genetic differences between animals and humans. The B6-hDMD (E49-53)*Del E50 mouse is a humanized model of the Dmd gene, in which the genomic sequences corresponding to exons 49–53 and their flanking regions in the mouse Dmd gene have been replaced with the corresponding human DMD gene sequences, followed by knock-out of exon 50 in the human DMD gene within the mouse genome. This model is suitable for research on Duchenne muscular dystrophy. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen provides other humanized models such as [hE49-53], [hE44-45, c.6438+2 T to A], [hE8-30], covering most popular research areas and offering customized services based on different mutation needs.

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 conditions such as obesity ^[5-7]. RNAi drugs primarily include small interfering RNA (siRNA) and antisense oligonucleotides (ASO). siRNA targets and degrades specific mRNA, while ASO binds to the target mRNA, preventing its translation or inducing its degradation, thereby inhibiting the expression of the target gene. Considering the genetic differences between humans and animals, humanizing mouse genes can accelerate the clinical development of RNAi therapies targeting human INHBE. This strain is a mouse Inhbe gene humanized model and can be used to study therapies targeting INHBE for obesity. The homozygous B6-huINHBE mice 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 for specific mutations to meet the experimental needs in pharmacology and other fields.

Interleukin 17A (IL-17A) is a signature cytokine of the T helper 17 (Th17) subset of CD4+ T cells and one of the six members (IL-17A~IL-17F) of the IL-17 family. IL-17A is primarily produced by Th17 cells and can also be produced by other immune cells under certain conditions, including CD8+ T cells, γδT cells, natural killer T (NKT) cells, monocytes, neutrophils, and microglia ^[1]. IL-17A mediates downstream pathways that induce the production of inflammatory molecules, chemokines, antimicrobial peptides, and remodeling proteins, which have important effects on host defense, cell transport, immune regulation, and tissue repair, especially in inducing innate immune defense. In healthy skin, commensal microorganisms induce the production of IL-17A to provide antifungal protection. When the skin barrier is damaged, IL-17A promotes epithelial cell proliferation and can clear pathogenic factors, promoting tissue repair and wound healing ^[2]. IL-17A usually protects the body when it is acutely injured, but when a wound requires long-term healing and becomes a chronic injury, the role of IL-17A may transform into wound erosion or excessive proliferation, ultimately leading to loss of function ^[3]. IL-17A plays a key role in various infectious diseases, inflammations, autoimmune diseases, and cancers. Its high expression level is associated with chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis. Lung injury caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely the result of the promotion of inflammatory reactions by cytokines such as IL-17A. Dysregulation of IL-17 signaling promotes pathogenic inflammation. IL-17A has a pathogenic role in mediating the important inflammatory pathway of psoriasis. The IL-23/Th17/IL-17A pathway is a key link in its pathogenesis, and inhibiting the expression of IL-17A can effectively alleviate psoriasis ^[4]. IL-17A is also associated with the course of ankylosing spondylitis (AS), and IL-17A inhibitors can effectively treat AS ^[5]. In addition, studies have shown that IL-17A is involved in the pathogenesis of neurodegenerative diseases in the central nervous system, and its expression level is related to the severity and progression of the disease ^[3]. The IL17F gene, located on chromosome 6p12.2, is primarily expressed by activated T cells, particularly Th17 cells, as well as other immune cells like γδ T cells and some innate immune cells ^[6]. The gene encodes the interleukin-17F (IL-17F) cytokine, a disulfide-linked homodimer protein that shares significant sequence homology with IL-17A ^[7]. Functionally, IL-17F is a pro-inflammatory cytokine that binds to the IL-17RA/RC receptor complex, triggering downstream signaling pathways involving Act1 and TRAF6, leading to the induction of various cytokines (like IL-6, IL-8, GM-CSF) and chemokines, which contribute to neutrophil recruitment and inflammation in barrier tissues such as the skin, lungs, and gut ^[8]. Elevated levels or dysregulation of IL-17F have been implicated in the pathogenesis of several autoimmune and inflammatory diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease (like Crohn's disease and ulcerative colitis), and potentially Sjögren's syndrome, highlighting its role in chronic inflammatory processes ^[7-9]. The B6-huIL17A/huIL17F mouse is a dual-gene humanized model constructed by gene-editing technology. Based on the B6-hIL-17A mouse (catalog number: C001510), the sequences from the ATG start codon to the TGA stop codon of the endogenous mouse Il17f gene were replaced with the sequences from the ATG start codon to the TAA stop codon of the human IL17F gene. This model can be used for research on the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis (RA), psoriasis, multiple sclerosis, and inflammatory bowel diseases (IBD) and the related therapeutic drugs, as well as for the development of IL17A/IL17F-targeted drugs.

The DMPK gene provides instructions for producing dystrophia myotonica protein kinase, a serine/threonine kinase that is primarily expressed in skeletal muscle, cardiac muscle, and the central nervous system, with lower levels found in smooth muscle and other tissues. This protein serves as a critical regulator of cellular processes, including the maintenance of muscle structure, ion channel gating (specifically sodium and calcium channels), and intracellular signaling pathways related to cytoskeletal dynamics and mitochondrial health. The gene is famously associated with Myotonic Dystrophy Type 1 (DM1), a multisystemic disorder caused by an unstable CTG trinucleotide repeat expansion in the 3' untranslated region (3'UTR) ^[1]. In healthy individuals, this sequence repeats between 5 and 37 times, but pathogenic expansions exceeding 50 repeats—sometimes reaching thousands—lead to the production of toxic "gain-of-function" RNA ^[2]. This mutant RNA accumulates in nuclear foci, sequestering critical splicing proteins (like MBNL1) and resulting in a wide array of clinical features, including progressive muscle wasting, myotonia (the inability to relax muscles), cardiac conduction defects, cataracts, and endocrine dysfunctions such as insulin resistance ^[3]. The B6-huDMPK mouse is a humanized model constructed through gene-editing technology, in which the sequences upstream of exon 1 to intron 10 of the mouse Dmpk gene are replaced with the sequences from upstream of exon 1 to downstream of the human DMPK gene. This model can be used for research on Myotonic Dystrophy Type 1 (DM1), cardiac conduction defects, cataracts, and endocrine dysfunctions such as insulin resistance, as well as for screening, development, and preclinical evaluation of DMPK-targeted therapeutics.

The FGFR1 gene provides instructions for the synthesis of the fibroblast growth factor receptor 1, a member of the receptor tyrosine kinase (RTK) family. This protein is characterized by an extracellular region with three immunoglobulin-like domains for ligand binding, a single transmembrane segment, and an intracellular tyrosine kinase domain that triggers downstream signaling cascades like the MAPK/ERK and PI3K/AKT pathways. FGFR1 is widely expressed across diverse tissues, with particularly high levels in the developing mesoderm, skeletal system, and the central nervous system, where it is essential for the migration of gonadotropin-releasing hormone (GnRH) neurons and olfactory bulb development ^[1]. Functionally, it acts as a master regulator of cell proliferation, differentiation, and survival, playing a pivotal role in embryonic limb induction and adult tissue homeostasis ^[2]. Mutations or chromosomal aberrations in FGFR1 are linked to a diverse array of diseases: gain-of-function mutations cause craniosynostosis syndromes like Pfeiffer and Jackson-Weiss syndromes, while loss-of-function variants lead to Kallmann syndrome (characterized by delayed puberty and an absent sense of smell) ^[3]. Additionally, FGFR1 gene amplifications and rearrangements are significant oncogenic drivers in various cancers, including squamous cell lung cancer, certain breast cancers, and 8p11 myeloproliferative syndrome ^[4]. The B6-huFGFR1 mouse is a humanized model constructed through gene-editing technology, in which the mouse Fgfr1 endogenous extracellular domain genomic DNA is replaced with the human FGFR1 extracellular domain genomic DNA. This model can be used for research on craniosynostosis syndromes, Kallmann syndrome, and various cancers, as well as for screening, development, and preclinical evaluation of FGFR1-targeted therapeutics.

The IL15 gene encodes a pleiotropic four-α-helix bundle cytokine known as Interleukin-15 (IL-15), which is essential for the development, survival, and activation of immune cells, particularly Natural Killer (NK) cells and memory CD8+ T cells. Unlike many cytokines, IL-15 is primarily regulated at the post-transcriptional and translational levels rather than just transcriptionally, and it is uniquely delivered to target cells through trans-presentation, where it is shuttled to the cell surface bound to its high-affinity receptor, IL-15Rα ^[1]. The protein is widely expressed across a variety of tissues, including the placenta, skeletal muscle, kidney, lung, and heart, and is produced by both hematopoietic cells (such as monocytes, macrophages, and dendritic cells) and non-hematopoietic cells (such as epithelial cells and fibroblasts) ^[2]. Functionally, IL-15 triggers the JAK/STAT (specifically JAK1/3 and STAT3/5) and PI3K/AKT/mTOR signaling pathways to promote cellular proliferation and inhibit apoptosis by upregulating anti-apoptotic factors like BCL2 ^[3]. Because of its potent inflammatory effects, dysregulation of the IL15 gene is implicated in several pathologies: over-expression is strongly associated with autoimmune diseases like Celiac disease, Rheumatoid Arthritis, and Multiple Sclerosis, as well as certain malignancies like Adult T-cell Leukemia, while its deficiency can lead to severe immunodeficiency or impaired response to viral infections ^[4]. The B6-huIL15 mouse is a humanized model constructed through gene-editing technology, in which the region from partial intron 4 to TGA stop codon of mouse Il15 is replaced with the region from partial intron 4 to TGA stop codon of human IL15. This model can be used for research on autoimmune diseases like Celiac disease, Rheumatoid Arthritis, and Multiple Sclerosis, as well as certain malignancies like Adult T-cell Leukemia. Furthermore, it serves as a platform for the screening, development, and preclinical evaluation of IL15-targeted therapeutics.

Retinitis pigmentosa (RP) is a hereditary retinal disease with a global prevalence of approximately 1:5000-1:3000. RP is highly clinically and genetically heterogeneous, with mutations in the rhodopsin (RHO) gene causing approximately 25% of dominant RP ^[1]. The rhodopsin encoded by the RHO gene is closely associated with visual light transduction and GPCR downstream signals. Rhodopsin is essential for the transmission of light signals in the process of vision formation. Most RHO mutations lead to high levels of rhodopsin expression in photoreceptor cells, causing many mutant proteins to be abnormally located and aggregated in cells. This results in the apoptosis of photoreceptor cells, which cannot perform normal light signal transduction functions. Additionally, mutations in the RHO gene are associated with congenital stationary night blindness (CSNB) ^[2-6]. Current gene therapy targeting the RHO gene to treat retinitis pigmentosa includes ASO, CRISPR, and others. Applying fully humanized animal models will promote the further development of RHO-related potential therapies in clinical trials ^[7-12]. This strain is a mouse Rho gene humanized model, in which the endogenous mouse Rho gene is replaced by the human RHO gene carrying a P23H mutation to express human retinal proteins in mice. Therefore, the abnormal protein encoded by the human gene was expressed in mice, resulting in abnormal retinal appearance and function and visual defects in this model. Based on the self-developed technological innovation of TurboKnockout fusion BAC recombination, Cyagen can also provide customized services for different point mutations to meet the needs of a wide range of R&D personnel regarding the pharmacodynamics of retinitis pigmentosa (RP) and other preclinical needs. Mutations in the RHO gene can lead to rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP). In 25% of autosomal dominant inherited RP (adRP) cases, there are over 150 different RHO gene mutations. Notably, the P23H mutation is one of the most prevalent, accounting for 10% of adRP cases ^[2]. Previous studies have shown that mice carrying the heterozygous human RHO P23H mutation exhibit retinopathy and progressive retinal degeneration similar to the patient's disease process, which could be used for visual signaling and retinitis pigmentosa (RP) studies ^[3]. B6-hRHO-P23H homozygous mice develop the disease earlier and have a more severe phenotype than heterozygous mice. Considering the uncertainty of growth and survival of homozygous mice due to late blindness, it is recommended to use B6-hRHO-P23H heterozygous mice for experiments. However, homozygous mice may also be selected for research according to specific experimental needs.

Retinitis pigmentosa (RP) is a hereditary retinal disease with a global prevalence of approximately 1:5000-1:3000. RP is highly clinically and genetically heterogeneous, with mutations in the rhodopsin (RHO) gene causing approximately 25% of dominant RP ^[1]. The rhodopsin encoded by the RHO gene is closely associated with visual light transduction and GPCR downstream signals. Rhodopsin is essential for the transmission of light signals in the process of vision formation. Most RHO mutations lead to high levels of rhodopsin expression in photoreceptor cells, causing many mutant proteins to be abnormally located and aggregated in cells. This results in the apoptosis of photoreceptor cells, which cannot perform normal light signal transduction functions. Additionally, mutations in the RHO gene are associated with congenital stationary night blindness (CSNB) ^[2-6]. Current gene therapy targeting the RHO gene to treat retinitis pigmentosa includes ASO, CRISPR, and others. Applying fully humanized animal models will promote the further development of RHO-related potential therapies in clinical trials ^[7-12]. This strain is a humanized model of the Rho gene with a heterozygous P23H mutation. It is obtained by mating homozygous B6J-hRHO mice (Catalog Number: C001396) with homozygous B6-hRHO-P23H mice (Catalog Number: C001495). In this model, the mouse Rho gene is replaced by the human RHO gene carrying the pathogenic mutation (P23H) and the human RHO gene without the mutation, respectively. The abnormal protein encoded by the mutant human gene is expressed in the mice. Therefore, the model exhibits abnormalities in the appearance and function of the retina, as well as visual defects. In addition, based on the technological innovation of TurboKnockout combined with BAC recombination developed independently, Cyagen Biosciences can also provide customized services for different point mutations based on B6-hRHO humanized mice to meet the experimental needs related to retinitis pigmentosa (RP) diseases. Mutations in the RHO gene are a major cause of RHO-mediated autosomal dominant retinitis pigmentosa (RHO-adRP). In 25% of autosomal dominant RP (adRP) cases, over 150 different RHO gene mutants have been identified. The P23H mutation is one of the most common causes of autosomal dominant retinitis pigmentosa, accounting for approximately 10% of adRP cases ^[2]. Previous studies have demonstrated that heterozygous mice carrying this mutation exhibit retinal pathology and progressive retinal degeneration similar to the disease progression in patients ^[3], making them valuable for studying visual signal transduction and retinitis pigmentosa (RP). Homozygous mice develop the disease earlier and have more severe phenotypes compared to heterozygous mice. Considering the uncertainty of the growth status and survival period of homozygous mice due to blindness in the later stage, it is generally recommended to use heterozygous mice (B6-hRHO*P23H/hRHO, Catalog Number: C001517) for experiments.

Retinitis pigmentosa (RP) is a hereditary retinal disease with a global prevalence of approximately 1:5000-1:3000. RP is highly clinically and genetically heterogeneous, with mutations in the rhodopsin (RHO) gene causing approximately 25% of dominant RP ^[1]. The rhodopsin encoded by the RHO gene is closely associated with visual light transduction and GPCR downstream signals. Rhodopsin is essential for the transmission of light signals in the process of vision formation. Most RHO mutations lead to high levels of rhodopsin expression in photoreceptor cells, causing many mutant proteins to be abnormally located and aggregated in cells. This results in the apoptosis of photoreceptor cells, which cannot perform normal light signal transduction functions. Additionally, mutations in the RHO gene are associated with congenital stationary night blindness (CSNB) ^[2-4]. Current gene therapy targeting the RHO gene to treat retinitis pigmentosa includes ASO, CRISPR, and others. Applying fully humanized animal models will promote the further development of RHO-related potential therapies in clinical trials ^[5-10]. This strain is a mouse Rho gene humanized model, in which the mouse Rho gene is replaced by the human RHO gene. The protein encoded by the human gene is normally expressed in the mouse. Therefore, the structure and function of the retina of this model are identical to those of wild-type mice, and there is no visual defect. This model can be used to study visual signaling and retinitis pigmentosa (RP). Based on the self-developed technological innovation of TurboKnockout fusion BAC recombination, Cyagen can also provide popular point mutation disease models constructed based on this model. The data shows that B6J-hRHO-P23H mice carrying a human RHO pathogenic mutation constructed based on B6J-hRHO mice exhibit a distinct retinal abnormal phenotype. Additionally, Cyagen can provide customized services for different point mutations to meet the needs of a wide range of R&D personnel regarding the pharmacodynamics of retinitis pigmentosa (RP) and other preclinical needs.

The MSH3 gene is a critical component of the post-replicative DNA mismatch repair (MMR) system that maintains genomic stability. It encodes the MSH3 protein, which serves as a housekeeping protein and is ubiquitously expressed at low levels across a wide range of human tissues, including the colon, rectum, small intestine, brain, and reproductive organs ^[1]. The protein primarily functions by forming a heterodimer with MSH2 to create the MutSβ complex, which is specialized in recognizing and initiating the repair of large insertion-deletion loops (IDLs) and dinucleotide or longer microsatellite repeats. Beyond its canonical MMR role, MSH3 is involved in homologous recombination and the repair of DNA double-strand breaks, contributing to cellular resistance against platinum-based chemotherapeutics ^[2]. Furthermore, MSH3 has been identified as a key genetic modifier of repeat expansion diseases, such as Huntington’s disease and myotonic dystrophy type 1, where its activity paradoxically promotes the somatic expansion of toxic CAG/CTG repeats, thereby influencing disease onset and progression ^[3]. The B6-huMSH3 mouse is a humanized model constructed through gene-editing technology, in which the exon 7 to downstream of exon 24 of mouse Msh3 is replaced with the entire human MSH3 gene plus human MSH3 promoter and downstream region, and the human sequence is inserted in reverse to prevent disruption of the Dhfr gene function. This model can be used for research on Huntington’s disease (HD) and myotonic dystrophy type 1 (DM1), as well as for screening, development, and preclinical evaluation of MSH3-targeted therapeutics.