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Mapping Disease Pathways for Biliary Atresia (BA)

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ClinicalTrials.gov Identifier: NCT03273049
Recruitment Status : Recruiting
First Posted : September 6, 2017
Last Update Posted : December 5, 2023
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Rakesh Sindhi, University of Pittsburgh

Study Description
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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.

Condition or disease
Biliary Atresia

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 Design
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Study Type : Observational
Estimated Enrollment : 1100 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Coordinating Center- Mapping Disease Pathways for Biliary Atresia
Actual Study Start Date : July 21, 2016
Estimated Primary Completion Date : December 21, 2025
Estimated Study Completion Date : July 21, 2027

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Outcome Measures
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Primary Outcome Measures :
  1. Genomic pathways of BA [ Time Frame: 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 :
  1. Predisposition of BA [ Time Frame: 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.


Biospecimen Retention:   Samples With DNA
Samples with DNA: blood, saliva or liver tissue.

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Individuals who have had a liver transplantation due to a diagnosis of biliary atresia.
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03273049


Contacts
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Contact: Morgan L Paul, BSN 4126928472 Morgan.Paul2@upmc.edu
Contact: Daniel Pieratt, MPA 4126926692 pierattdw@upmc.edu

Locations
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United States, Pennsylvania
UPMC Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Morgan L Paul, BSN    412-692-8472    Morgan.Paul2@upmc.edu   
Contact: Daniel Pieratt, MPA    4126926692    pierattdw@upmc.edu   
Principal Investigator: Rakesh Sindhi, MD         
Sponsors and Collaborators
University of Pittsburgh
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
More Information
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Responsible Party: Rakesh Sindhi, Rakesh Sindhi, MD, Professor of Surgery, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03273049    
Other Study ID Numbers: STUDY19070273
1R01DK109365-01A1 ( U.S. NIH Grant/Contract )
First Posted: September 6, 2017    Key Record Dates
Last Update Posted: December 5, 2023
Last Verified: December 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Biliary Atresia
Bile Duct Diseases
Biliary Tract Diseases
 Digestive System Diseases
Digestive System Abnormalities
Congenital Abnormalities