Researchers Develop Lab-Grown Miniature Bile Ducts and Discover Effective Drug Against Cystic Fibrosis

A new study recently published in the journal Nature Biotechnology reported the creation of miniature bile ducts in the lab and their use in the discovery of a new promising therapeutic drug for cystic fibrosis (CF). The study is entitled “Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation” and was led by researchers at the Wellcome Trust-Medical Research Council Stem Cell Institute and the Wellcome Trust Sanger Institute in Cambridge.

CF is a rare, life-threatening genetic disease in which a defective gene (CFTR) induces a salt imbalance, causing the body to form unusually thick, sticky mucus that can obstruct the airways and promote dangerous lung infections resulting in serious respiratory and also gastrointestinal manifestations. The majority of the CF patients die due to respiratory failure. It is estimated that almost 75,000 individuals worldwide suffer from CF, including 30,000 individuals in the United States.

The loss of function of the CFTR gene in the biliary epithelium leads to a reduction in bile flow, with CF patients often experiencing ductal cholestasis, a condition where the bile cannot flow from the liver to the duodenum. The study of biliary disorders, including CF-associated cholestasis, has been impaired by the lack of primary human cholangiocytes (epithelial cells of the bile duct) models.

In the study, researchers presented an effective, serum-free method for direct differentiation of cholangiocyte-like cells (CLCs) from human induced pluripotent stem cells, which correspond to immature cells that have the potential to differentiate into several specialized cell types. Through this technique, researchers were able to grow and recreate fully functional three-dimensional bile ducts in the lab.

“The bile duct cells we have generated represent an invaluable tool to understand not only how healthy bile ducts develop and function, but to also understand how diseased bile ducts behave and how they may respond to therapeutic treatment. This platform opens up the possibility of modeling complex liver diseases and will certainly progress our understanding of biliary disease in the future,” noted the study’s co-senior author Dr. Nicholas Hannan in a news release.

The team used their lab-grown miniature bile ducts and tested several drugs for biliary diseases. In this analysis, researchers found that one of the experimental drugs developed for the treatment of the CF effects in the lungs, VX809 (also known as Lumacaftor, one of the two drugs in Vertex’s newly approved combination therapy Orkambi), could indeed prevent the damage caused by the disease to the liver and bile duct.

“Treating liver complications caused by bile duct disorders constitutes a major challenge — with the only treatment option often being liver transplantation. We were delighted to identify a new experimental drug that could prevent patients with cystic fibrosis, one of the most common inherited disorders in Europe, from undergoing a liver transplantation, a major and life changing operation. But, this treatment will need to be tested in clinical trials before it can be recommended to patients,” said the study’s lead author Dr. Fotios Sampaziotis.

The research team proposes that their lab-grown miniature bile ducts could be a valuable tool for the study of biliary disease modeling and drug screening. “The pharmaceutical applications of our system are particularly important as we don’t have many human samples of this type of tissue to work on. This system could provide a unique resource for identifying new therapeutic agents,” concluded the study’s co-senior author Dr. Ludovic Vallier.