Progressive Familial Intrahepatic Cholestasis (PFIC) is a severe, autosomal recessive liver disorder marked by genetic mutations affecting hepatocellular bile acid secretion. PFIC affects approximately 1 in 50,000 to 1 in 100,000 live births globally1. Among the PFIC variants, PFIC2, which results from mutations in the ABCB11 gene, accounts for nearly half of the cases. Patients with PFIC2 suffer from progressive liver failure, cirrhosis, and a high risk of developing hepatocellular carcinoma.
Effective pre-clinical models are essential for drug discovery and development. Traditional models, such as ABCB11 knock out mouse models, human primary hepatocytes, or liver carcinoma cell lines (e.g., HepG2), all come with significant limitations:
Mouse Models: While useful for modeling certain disease states, mouse models seem unsuitable for studying PFIC2, as they often exhibit compensatory mechanisms, including increases in the expression of alternative bile acid transporters (e.g., ABCB1/MDR1), an effect that is not observed in patients with PFIC22. This core difference between mouse models and human physiology reduces the predictive accuracy of any drug candidate screened against these model systems.
Primary Human Hepatocytes: Given the rarity of PFIC2, access to patient-derived cells is limited, rendering the modelling of the disease using primary human hepatocytes difficult. In addition, significant donor-to-donor variation between patients introduces an additional element of variability in establishing a reliable cellular model for this disease. These factors make primary cells insufficient for large-scale drug screening studies.
Carcinoma Cell Lines: Commonly used cell lines, such as HepG2, do not express the ABCB11 transporter, making them phenotypically irrelevant for PFIC2 research.
iPSC-Derived PFIC2 Cells: DefiniGEN has developed the world’s first human-induced pluripotent stem cell (iPSC)-derived hepatocyte system that accurately models the PFIC2 phenotype. Through CRISPR-Cas9 technology, the D482G mutation has been introduced into the ABCB11 gene of these iPSC-derived hepatocytes. Using this technology, researchers can acquire a phenotypically relevant, accurate, and consistent cellular disease model that demonstrates no batch-to-batch variation. Crucially, and by leveraging the benefits of the iPSC technology, scientists can have access to an unlimited number of cells, allowing for the large-scale drug screening for efficacy and toxicity studies.
1. Biological Relevance: iPSC-derived PFIC2 cells exhibit proper cellular polarization, with reduced ABCB11 mRNA and protein expression levels, disrupted ABCB11 localization, and impaired bile acid transport, accurately mimicking the human disease phenotype.
2. Consistency and Reproducibility: Sourced from a single donor, these cells ensure no batch-to-batch variation, providing highly reproducible data crucial for drug screening.
3. Scalability: Unlike primary cells, iPSC-derived hepatocytes can be produced in large quantities, meeting the demands of extensive screening programs.
DefiniGEN’s iPSC-derived PFIC2 cells offer a biologically accurate, reproducible, and scalable solution for PFIC2 research and drug screening. Our cells address the shortcomings of mouse models, primary liver cells, and carcinoma liver cell lines, making them an indispensable tool for advancing PFIC2 therapeutics. For standardized, phenotypically relevant PFIC2 human models, contact one of our experts today.
References
1. Progressive Familial Intrahepatic Cholestasis Overview
2. ABCB11 Gene and PFIC2