Congratulations to Professor Paul Tam and Dr. Vincent Lui for the award of 11th round Theme-based Research Scheme (TRS), of which project entitled "Translating Disease-Mechanism Discoveries to Improve Treatment of Biliary Atresia, an Intractable Newborn Liver Disease"!
Project Title: Translating Disease-Mechanism Discoveries to Improve Treatment of Biliary Atresia, an Intractable Newborn Liver Disease
Project Coordinator: Prof Vincent Chi Hang Lui (HKU)
Abstract
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 pathogenetic mechanisms. We are a new BA consortium, which comprises a team of clinicians and scientists, strengthened by the addition of international experts with unique complementary expertise, who are poised to pioneer BA research, diagnosis and therapy. Building on our promising discoveries recently published in J Hepatol, we propose to advance BA research to 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 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 amyloid-beta deposition, ciliary dysfunction (our new findings); immune-inflammation and fibrosis. The findings will inform clinicians on patient stratification and provide evidence for implementing 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 a devastating liver disease and enhance its diagnostics and therapy development. Advances in this project also serve as a model for discovery research of other gastrointestinal diseases.
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