Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3) is a rare, life-threatening autosomal recessive hereditary liver disease caused by mutations in the ABCB4 gene (also known as MDR3 in humans and MDR2 in rodents) ^[1-3]. The disease is characterized by early persistent cholestasis, leading to the accumulation of bile acids in the liver and subsequent hepatocellular damage. Clinical manifestations of PFIC3 include jaundice (yellowing of the skin and eyes), pruritus, fatigue, and growth failure. If untreated, it can progress to cirrhosis and liver failure in early childhood ^[4]. The ABCB4 gene encodes Multidrug Resistance Protein 3 (MDR3), a member of the ATP-binding cassette (ABC) transporter family, which is a liver-specific phosphatidylcholine (PC) transporter ^[5]. MDR3 is primarily expressed on the canalicular membrane of hepatocytes (the membrane that forms bile canaliculi). It is involved in the transport of phosphatidylcholine from the hepatocyte membrane to vesicles, which are then secreted into bile, forming PC-cholesterol vesicles and a small number of mixed bile salt micelles ^[6]. Mutations in ABCB4 lead to the loss or dysfunction of MDR3, reducing PC levels in bile, destabilizing micelles, and increasing bile salt concentrations, thereby causing cholestasis and hepatocellular injury ^[7].

Studies have shown that knocking out the Abcb4 gene in mice leads to a phenotype similar to human PFIC3, although the severity and progression of the disease vary across different mouse strains. In the commonly used C57BL/6 background, Abcb4-KO mice exhibit a relatively mild pathological phenotype due to lower bile salt toxicity, and a diet enriched in hydrophobic bile salts is typically required to induce a more human-like PFIC3 phenotype ^[8-10]. In contrast, Abcb4-KO mice in the FVB background naturally exhibit most of the biomarkers and pathological features of human PFIC3, including hepatomegaly, liver fibrosis, and early disease onset with more severe progression ^[10-11].

Cyagen has generated the FVB-Abcb4 KO mouse model by knocking out the Abcb4 gene in FVB mice. This model lacks the Abcb4 gene and protein expression and exhibits liver enlargement, elevated liver function markers, and increased total bilirubin. Histopathological examination shows hepatocyte necrosis, inflammatory cell infiltration, connective tissue proliferation, bile duct proliferation, and liver fibrosis.