Mapping Disease Pathways for Biliary Atresia

Recruiting

• Conditions: Biliary Atresia

• Registration Number: NCT03273049
• Lead Sponsor: University of Pittsburgh

Brief Summary

This project will primarily evaluate the developmental/genetic basis of biliary atresia, the most common cause of liver failure at birth, and which accounts of half of all liver transplants performed worldwide in children.

Detailed Description

Characterized by failure to drain bile from the liver due to atretic extrahepatic bile ducts, BA is corrected in less than half of all affected children with surgical reconstruction. The remainder progress to cirrhosis and require liver transplantation. Because bile duct loss can be accompanied by other birth defects such as laterality defects of the gut and cardiovascular systems, the disease has been categorized into the more common 'isolated' variety presumably due to a perinatal viral cholangitis, and the 'syndromic' variety, due to genetic factors. Mechanistic differences implied by this categorization have not been demonstrated conclusively. In contrast, three susceptibility genes identified in predominantly 'isolated" BA cases, and the presence of abnormal cilia which are known to predispose to laterality defects, in both isolated and syndromic forms of BA suggest that in addition to environmental influences, genetic susceptibility is important in both forms of BA. This view is reinforced by our preliminary work which shows that knockdown of a novel BA susceptibility gene causes both biliary dysgenesis and laterality defects in animal models. This finding also suggests that common birth defects affecting the liver and other organs may originate from defects in the same genes. The project will combine candidate gene identification and replication with human DNA samples from 1100 BA subjects and their biological parents or siblings, if available, with validation using corresponding human BA liver tissue and zebrafish knockdown models.

The project outcome will consist of pathways comprising multiple susceptibility genes involved in morphogenesis of the liver and other organs, which explain the complex phenotype of BA. The project will use the experimental and bioinformatics capabilities of the Universities of Pittsburgh and California (at San Diego) to analyze data and study human samples from the participating centers. Four of the world's largest pediatric liver transplant centers, the Children's Hospitals of Pittsburgh (CHP), King's College Hospital (KCH), London, UK, Birmingham Children's Hospital, UK (BCH), and the Hospital Sirio Libanes (HSL), Sao Paulo, Brazil will enroll biliary atresia subjects and their biological parents and/or siblings, if available.

Information developed in this project will be the basis for designing novel management strategies to reduce the societal impact of this rare childhood disease.

Study Timeline

• Study Start: 2016-07-21
• Study First Submitted: 2017-09-01
• Study First Submitted QC: 2017-09-01
• Study First Posted: 2017-09-06
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-02
• Last Update Posted: 2024-10-04
• Primary Completion: 2030-12-21
• Study Completion: 2035-07-21

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1100

Inclusion Criteria

• living individuals who were diagnosed with Biliary Atresia and received or are about to receive a liver transplant from multiple participating centers (Children's Hospital of Pittsburgh, Kings College Hospital, Children's Hospital of Birmingham, and Hospital Sírio-Libanês).

Exclusion Criteria

• No child participant in the care of the state will be enrolled, nor will patients in the care of temporary or informal guardians be enrolled

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Genomic pathways of BA	up to two years	Main project outcome will consist of pathways comprising multiple susceptibility genes involved in morphogenesis of the liver and other organs, which explain the complex phenotype of BA.

Secondary Outcome Measures

Name	Time	Method
Predisposition of BA	upwards of four years to achieve this outcome measure	determine whether candidate genes and related pathways which predispose to BA, also predispose to laterality defects affecting the liver and other organs.

Trial Locations

Locations (1)

UPMC Children's Hospital of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States