Rare Disease

• Disease: Phenylketonuria

• Genetic Background: C57BL/6JGpt

• Construction Method: CRISPR/Cas9 knockout of the Pah gene.

• Key Phenotypic Characteristics: Homozygous mice develop severe hyperphenylalaninemia. Upon switching from a low-phenylalanine diet to a regular diet, serum phenylalanine levels reach 1600 μM, recapitulating the severe biochemical hallmark of PKU.

• Molecular/Protein Validation: Western blot analysis confirms complete absence of Pah protein expression in both liver and kidney tissues of homozygous knockout mice compared to wild-type controls.

Applications: Essential for research into PKU disease mechanisms and for the preclinical evaluation of dietary therapies, enzyme replacement therapies, and gene therapies targeting phenylalanine metabolism.

• Disease: Tyrosinemia Type I

• Genetic Background: C57BL/6JGpt

• Construction Method: CRISPR/Cas9 knockout of the Fah gene.

• Key Phenotypic Characteristics: Mice develop spontaneous tyrosinemia. Withdrawal of the protective drug NTBC leads to hepatorenal toxicity, manifested by swollen liver and kidney and significantly elevated serum ALT, AST, and total bilirubin (TBIL) levels.

Molecular/Protein Validation: No Fah protein is detected in liver or kidney tissues via specific assays.

Histopathological Findings: Liver and kidney sections reveal lesions characterized by infiltration of fibroblasts and lymphocytes, along with vacuolar degeneration of hepatocytes.

Applications: A robust model for studying tyrosinemia pathogenesis and testing hepatoprotective agents, liver-directed gene therapy, and novel enzyme stabilizers.

• Disease: Hepatolenticular Degeneration

• Genetic Background: C57BL/6JGpt

• Construction Method: CRISPR/Cas9 knockout of the Atp7b gene.

• Key Phenotypic Characteristics: Homozygous mice exhibit profound copper metabolism dysfunction. This includes a significant decrease in serum ceruloplasmin activity and a marked increase in urinary copper excretion following intraperitoneal injection of CuSO₄.

• Histopathological Findings: Liver pathology is prominent, featuring hepatocellular steatosis (fatty change) and noticeable hepatocyte enlargement.

• Applications: The premier model for investigating copper chelation therapy, evaluating novel ATP7B gene correction strategies, and studying the progression of hepatic and neurological damage in Wilson's disease.

• Disease: Progressive Familial Intrahepatic Cholestasis Type 3

• Genetic Background: C57BL/6JGpt

• Construction Method: CRISPR/Cas9 knockout of the Abcb4 gene.

• Key Phenotypic Characteristics: Mice aged 6-8 weeks show significantly elevated serum markers of liver injury: ALT, AST, and TBIL.

• Histopathological Findings: Liver histology reveals a progressive cholestatic phenotype including periportal and interstitial fibrosis, inflammatory cell infiltration around portal tracts, bile duct proliferation, and hepatocyte degeneration and necrosis. This pathological profile worsens with age.

• Applications: Critical for modeling PFIC3 and testing novel choleretic agents, anti-fibrotic therapies, and gene-based interventions aimed at restoring biliary phospholipid secretion.

• Genetic Background: C57BL/6JGpt

• Construction Method: CRISPR/Cas9 knockout of the Col7a1 gene.

• Key Phenotypic Characteristics: Homozygous mice display a severe neonatal lethality phenotype. Survivors exhibit severe abdominal congestion and wrinkled skin in the neck region as early as postnatal day 2 (P2).

• Applications: A critical model for the severe recessive form of DEB, used for testing protein replacement therapies, gene editing approaches to restore COL7A1 expression, and advanced wound care strategies.

• Genetic Background: C57BL/6JGpt

• Construction Method: CRISPR/Cas9 knockout of the α-galactosidase A (Gla) gene.

• Key Phenotypic Characteristics: Mice exhibit significantly reduced GLA enzyme activity in the liver, kidney, heart, and brain. Correspondingly, GLA mRNA expression, Gb3 and Lyso-Gb3 levles  is significantly downregulated in the liver and brain.

• Applications: A model for Fabry disease, suitable for testing enzyme replacement therapy (agalsidase alfa/beta), chaperone therapy (migalastat), and next-generation gene therapies.