Interferons (IFNs) are potent cytokines that serve as a critical component of the body's first line of defense against viral infections, playing a key role in inflammation and immune control by directly inducing pathogen-inhibiting molecules that suppress viral replication ^[1]. Arthropod-borne viruses (arboviruses) like Dengue virus (DENV), Zika virus (ZIKV), and Yellow Fever virus (YFV) encode proteins that antagonize the IFN response, helping these viruses evade host immunity and maintain sufficient viral loads in the blood (viremia) to sustain the vector-host transmission. Arboviruses pose a significant public health threat, affecting around 3.9 billion people in tropical and subtropical regions. However, most preclinical studies suggest that arboviruses cannot inhibit IFN responses in mice, rendering immunocompetent mice resistant to infection, with low viral loads and limited circulation, thus limiting their use in infection research ^[2-3]. As a result, immunodeficient mouse models with defects in multiple IFN signaling pathways have become essential tools for studying arbovirus pathogenesis and vaccine development ^[2-4]. Studies have demonstrated that wild-type mice of strains like C57BL/6, CD-1, or 129 rarely exhibit clinical symptoms after infection with arboviruses such as ZIKV. However, the virus has been detected in the blood, ovaries, and spleen of ZIKV-infected 129 mice, suggesting that this strain may be more susceptible to arboviruses ^[5-6]. Because the virus can persist in the bloodstream without causing disease or death, the 129 strain can be used to evaluate the teratogenic effects of such viruses. Furthermore, the 129 strain is commonly used in interferon signaling-deficient models related to other viral infections ^[7-8]. The IFNAR1 gene encodes a key component of the type I IFN receptor, while the IFNGR1 gene encodes the ligand-binding chain (α) of the type II (γ) IFN receptor. AG129 mice, which are knockout models for both the type I (α/β) IFN receptor (Ifnar1) and the type II (γ) IFN receptor (Ifngr1), lack functional IFNAR1 and IFNGR1 proteins, resulting in deficiencies in α/β/γ interferon receptor signaling and heightened susceptibility to viral infections. Homozygous AG129 mice are viable and fertile, and exhibit increased sensitivity to arboviral infections, generating viremia similar to that seen in humans. Compared to IFNα/β/γR KO mice on the C57BL/6 background, the 129-background AG129 mice exhibit more pronounced neurological symptoms after infection ^[6,9].

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 ALMS1 gene encodes the large, multi-domain ALMS1 protein, which localizes primarily to the centrosomes and basal bodies of primary cilia within cells. There, it plays a critical role in microtubule organization, ciliogenesis, endosome recycling (notably of the GLUT4 transporter), and cell cycle regulation ^[1]. Because primary cilia are sensory organelles found on nearly all cell types, the gene is expressed across a wide range of tissues, including the retina, cochlea, pancreatic islets, adipose tissue, renal tubules, and cardiomyocytes. Mutations in ALMS1 lead to Alström syndrome in humans, a rare autosomal recessive ciliopathy marked by progressive multisystem failure, including cone-rod dystrophy (blindness), sensorineural hearing loss, childhood obesity, extreme insulin resistance, type 2 diabetes, and dilated cardiomyopathy ^[2]. Research on mice with Alms1 deficiency has successfully recapitulated the clinical features mentioned above, confirming that the loss of this gene leads to stunted renal cilia, impaired intracellular trafficking in photoreceptors, and metabolic dysfunction that mirrors human disease progression ^[3]. Furthermore, a high-fat diet (HFD) can accelerate the metabolic pathological process in Alms1 KO mice, making them more susceptible to metabolic diseases such as hyperglycemia, hyperinsulinemia, and insulin resistance, while also inducing hepatic inflammation and fibrosis ^[4]. Alms1-del(c.3802-3812) mice are a research model constructed using gene-editing technology to introduce a c.3802_3812 del CAAAAACAGTT mutation into exon 8 of the mouse Alms1 gene. Both homozygous female and male Alms1-del(c.3802-3812) mice were infertile. This model can be utilized for research into the pathological mechanisms and the development of therapeutic interventions for Alström syndrome, as well as metabolic diseases such as obesity, diabetes, and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

The adenomatous polyposis coli (APC) gene is a tumor suppressor gene, the protein it encodes plays a key regulatory role in the Wnt/β-catenin signaling pathway ^[1]. The APC protein can antagonize the Wnt signaling pathway, assisting in regulating cell migration, adhesion, transcriptional activation, and apoptosis. More than 10% of human tumors have mutations in the APC gene, and most colorectal cancers have mutations in the APC gene ^[2]. Defects in the APC gene lead to the occurrence of familial adenomatous polyposis (FAP), characterized by hundreds to thousands of adenomatous polyps in the rectum. This is an autosomal dominant precancerous disease, which usually develops into malignant tumors ^[1-2]. Disease-related mutations in the APC gene are highly prevalent in a small region known as the mutation cluster region (MCR), which usually leads to the production of truncated proteins ^[3-4]. In mice, either Apc gene deletion or multiple intestinal neoplasia (Min) mutations that result in the production of truncated APC proteins cause phenotypes similar to human familial adenomatous polyposis (FAP) and/or colorectal tumors ^[5-9]. The Apc KO mouse is a research model constructed by using gene editing technology to knock out the sequence in the mouse Apc gene that contains the mutation cluster region (MCR), and this strain is homozygous lethal. Heterozygous Apc KO mice can spontaneously develop intestinal adenomas and exhibit significant colorectal cancer disease phenotypes in various aspects such as survival, growth, food intake, and intestinal lesions. Therefore, Apc KO mice can be used for familial adenomatous polyposis (FAP) and colorectal cancer and other tumors or tumor-related diseases, as well as the study of the regulatory mechanism of the Wnt/β-catenin signaling pathway.

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.

Polycystin-1 (PC1), encoded by the PKD1 gene, is a large transmembrane glycoprotein that orchestrates critical cellular processes—including cell–cell and cell–matrix interactions, calcium signaling, and mechanosensation—in renal tubular epithelial cells. PC1 regulates various aspects of cellular function, including signal transduction, cytoskeletal remodeling, and cell adhesion. It forms a functional complex with Polycystin-2 (PC2), the product of the PKD2 gene, to maintain intracellular calcium homeostasis and facilitate mechanotransduction ^[1]. Disruption of PC1 signaling, due to PKD1 mutations—which account for approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases—undermines these regulatory pathways, promoting abnormal cell proliferation and cyst formation ^[2]. Clinically, ADPKD is characterized by the progressive development of multiple fluid-filled cysts, renal enlargement, hypertension, and eventual progression to end-stage kidney disease (ESKD). With a global incidence estimated at 1 in 400 to 1 in 1000 individuals, ADPKD affects nearly 500,000 people in the United States alone and frequently involves extra-renal manifestations, including the heart, liver, pancreas, spleen, and arachnoid membrane ^[3]. Notably, genotypic heterogeneity exists, with PKD1 mutations often associated with an earlier onset and more aggressive disease course ^[2-3]. Traditional systemic Pkd1 knockout models are typically embryonically lethal, precluding long-term pathogenesis studies. In contrast, inducible, kidney-specific conditional knockout models using the Cre-LoxP system recapitulate the clinical features of human ADPKD and permit the investigation of disease progression in adult mice ^[4-5]. Acute PKD (inducible) mice represent an inducible conditional Pkd1 knockout model generated by crossing Pkd1-floxed mice with kidney-specific, tamoxifen-inducible Cre mice (Cdh16-MerCreMer). Offspring were induced with tamoxifen during lactation to achieve targeted deletion of Pkd1 within renal tubular epithelial cells. Preliminary observations at three weeks post-induction reveal pronounced polycystic kidney disease phenotypes, including the emergence of renal cysts, a marked increase in kidney volume, and elevated serum blood urea nitrogen (BUN) levels. We will continue to monitor this model to assess its late-stage phenotypes and overall disease progression.

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 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.