Translating Disease-Mechanism Discoveries to Improve Treatment of Biliary Atresia, an Intractable Newborn Liver Disease

Biliary Atresia (BA) is a devastating inflammatory disease of the bile ducts affecting 5-20:100,000 newborns, with the highest frequency in Asians. BA diagnosis is challenging, sometimes missed or made late. Untreated, infants die from liver fibrosis and failure. Kasai surgery is the first line treatment but bile drainage is only achieved in 50% of patients. Moreover, Kasai surgery only replaces the extra-hepatic bile duct, and the intra-hepatic cholangiopathy is un-remedied. Hence patients often develop biliary infection and sclerosis, leading to liver failure requiring liver transplantation which presents challenges from organ shortage and long-term immunosuppression. BA thus represents a huge medico-societal problem, improved diagnosis and new therapies are therefore urgently warranted. The root cause for lack of progress in BA treatment lies in the poor knowledge of its underlying patho-mechanisms. We are however at the cusp of a new era in BA research, diagnosis and therapy thanks to some promising discoveries (published in J Hepatol) by a new BA consortium, which comprises a team of clinicians/scientists who have successfully completed a 5-year TRS project on another gastrointestinal disorder Hirschsprung’s disease (published in Gastroenterology, Genome Research, Lancet), strengthened by the addition of international experts with unique complementary expertise. We now propose to advance BA research to significantly improve our understanding of its disease mechanisms using novel, beyond state-of-the-art organoid-based systems, dissect disease heterogeneity through genomics and transcriptomics, and pursue novel therapeutic leads with pre-clinical testing. These ambitious goals will be achieved by a multi-pronged approach. We will 1) use cholangiocyte organoids from human livers/induced Pluripotent Stem Cells, multi-cell type organoids, and cells/organoids seeded onto liver extracellular matrix-derived gel to assess the pathobiological roles of various cell types, paracrine/guidance/matrix cues, toxins, virus, immune-inflammatory dysfunction and fibrosis; 2) integrate whole-exome (n=400 BA trios) and tissue transcriptomic (n=50) analyses with comprehensive clinical/phenotype information to stratify BA patients and discover novel disease mechanisms; 3) pursue targeted therapies, using BA organoids as clinical surrogates to test drug repurposing on beta-amyloid deposition, ciliary dysfunction (our new findings); immune-inflammation and fibrosis. The findings will inform clinicians in patient stratification and provide evidence for clinical trials of novel therapies towards regeneration of a functional biliary tree. In sum, by combining leading clinical expertise and cutting-edge technologies, we will break new grounds in the understanding of an important liver disease and improve its diagnostics and therapy development. Advances in this project can also serve as a model for discoveries in other gastrointestinal diseases.