Primary Biliary Cholangitis
Primary biliary cholangitis (PBC) is a complex autoimmune liver disease that requires a multidimensional approach for effective therapeutics. At our company, we are dedicated to advancing the field of PBC through our diagnostics development services, therapy development services, animal model development services, and preclinical research services.
Introduction to Primary Biliary Cholangitis
Primary biliary cholangitis (PBC), alternatively referred to as primary biliary cirrhosis, is a persistent autoimmune liver ailment marked by the gradual deterioration of the small bile ducts located within the liver. This condition predominantly affects women in their middle age and is characterized by the presence of antimitochondrial antibodies (AMA) in the bloodstream. PBC can give rise to severe complications, including liver cirrhosis, liver failure, and necessitating liver transplantation.
The destruction of bile ducts in PBC is primarily mediated by autoreactive T cells and the production of pro-inflammatory cytokines. These immune responses lead to chronic inflammation, cholestasis (impaired bile flow), and subsequent fibrosis in the liver. The exact mechanisms underlying the loss of immune tolerance and the specific targets of the autoimmune response in PBC are still under investigation.
Fig.1 Immune dysregulation in primary biliary cholangitis. (Gulamhusein A. F. et al. 2020)
Drug Discovery and Development for Primary Biliary Cholangitis
In the search for effective therapeutics for PBC, various drugs have been developed. The current standard of care is the use of ursodeoxycholic acid (UDCA), which has shown efficacy in improving liver biochemistry levels, delaying disease progression, and prolonging liver transplant-free survival. Obeticholic acid (OCA), a selective ligand of the farnesoid X receptor (FXR), has been approved as a second-line therapeutic for PBC. It has shown modest efficacy in reducing alkaline phosphatase (ALP) levels and normalizing bilirubin levels. Moreover, fibrates, such as bezafibrate and fenofibrate, have shown promise as add-on therapies to UDCA for patients with incomplete responses. These medications reduce bile acid synthesis and upregulate bile acid transporters, leading to improved liver biochemistry levels and liver stiffness.
Our multidisciplinary team of scientists and researchers works tirelessly to explore various drug classes, including small molecules, biologics, and gene therapies, to address the diverse needs of the pharmaceutical industry in the development of PBC therapies. If you would like to learn more about our therapeutic development solutions, please click on the links below.
Our Services
At our company, our diagnostics and therapeutic development services are dedicated to discovering and developing novel therapeutics for PBC. Preclinical research plays a fundamental role in the drug development process by providing crucial data on the safety, efficacy, and pharmacokinetic properties of potential therapeutics. We offer comprehensive preclinical research services to support the development of new therapeutics for PBC.
Genetic Engineering Models
We provide a variety of genetic engineering model development services, including dominant-negative TGF-β receptor II model, IL-2Ra−/− model, NOD.c3c4 model, AE2a,b−/− model, and ARE-Del−/− model, to support your PBC therapy research.
2-Octynoic Acid (2-OA)-Immunized Models
We offer 2-Octynoic Acid (2-OA)-immunized mouse development services. This model is developed by immunizing mice from the C57BL/6 background with 2-OA, a synthetic chemical mimic of the lipoic acid-lysine located in the PDC-E2 domain.
Poly I:C-Sensitized Models
Polyinosine polypeptidic acid (Poly I:C) is a synthetic molecule that mimics viral RNA and induces the production of type 1 interferons (IFNs). High IFN expression has been linked to the progression of autoimmune diseases, including PBC.
2-OA and Poly I:C Co-immunized Models
2-octynoic acid (2-OA) is conjugated to bovine serum albumin (BSA) and administered along with poly I:C, a synthetic double-stranded RNA. This model induces autoimmune cholangitis with characteristic features of PBC, including bile duct inflammation, AMA production, and T-cell activation.
Escherichia coli-Infected Models
Several studies have shown a connection between urinary tract infections, specifically those caused by Escherichia coli (E. coli), and an increased risk of PBC. To mimic this mechanism of cross-recognition induced by the PDC-E2 epitope in PBC, we offer E. coli-infected mouse models.
Bile Duct Protein (BDP)-Immunized Models
Bile duct protein (BDP)-immunized models are generated by immunizing mice, typically of the C57BL/6 background, with bile duct protein. This immune response leads to lymphocytic infiltration and elevated AMA levels, mimicking certain aspects of autoimmune cholangitis seen in PBC.
Cell-based model development plays a critical role in developing effective therapeutics. Our company provides comprehensive cell-based model development services, including hepatocyte-immune cell co-culture models, biliary epithelial cell models, and stromal cell models.
Our company offers organoid model development services to mimic the complex architecture and cellular interactions of the liver. These organoids can be used to study PBC-specific processes, such as bile duct destruction, immune cell infiltration, fibrosis development, and drug testing.
Customized Disease Models
Furthermore, at our esteemed company, we excel in providing bespoke solutions and crafting disease models that precisely cater to your unique specifications. We understand that each research project is distinct and may require tailored approaches to effectively study pemphigus vulgaris.
Our experienced team of scientists designs and executes preclinical studies, including in vitro assays and in vivo experiments, to evaluate the efficacy and safety profiles of drug candidates. In addition to the aforementioned services and models, we also provide customized solutions and develop disease models that cater specifically to your unique needs. If our services have piqued your interest, please do not hesitate to contact us.
Reference
- Gulamhusein, Aliya F., and Gideon M. Hirschfield. "Primary biliary cholangitis: pathogenesis and therapeutic opportunities." Nature Reviews Gastroenterology & Hepatology 17.2 (2020): 93-110.