Clinical Center for ChiLDREN: Pathogenesis, Biomarkers, and Antifibrotic Therapy

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DESCRIPTION (provided by applicant): The Childhood Liver Disease Research and Education Network (ChiLDREN) provides an unprecedented opportunity to improve the lives of children with serious liver diseases. Continued productive contributions of this Clinical Center to ChiLDREN are proposed with 3 major aims: I. Consortium Contribution: A well-organized infrastructure that enables a high level of patient enrollment and data and specimen collection is well established, integrated into one of the largest pediatric hepatology programs in the United States with experienced investigators and coordinators, and an excellent track record in clinical research. In addition, we propose leading an analysis of clinical data and biliary atresia liver tissue to better evaluate phenotypic and clinicopathological correlations and, by competing outcomes, multivariate and neural network modeling, to better predict and determine outcomes after hepatoportenterostomy. II. Ancillary Studies: Several unique studies are linked to this proposal, developing from this Clinical Center's pre-eminent strengths and preliminary studies: (i) serum fibrosis and novel imaging markers will be further evaluated to improve diagnosis and monitor liver fibrosis in ChiLDREN diseases; (ii) in parallel mechanistic studies, we are further exploring the molecular mechanisms of pathogenesis of biliary atresia and CFLD, studying epigenetic, genetic, and fundamental fibrogenetic mechanisms in liver tissue and serum, and we propose extending these studies to repository tissue and data analysis. III. Clinical Trial: To evaluate new antifibrogenic therapies, a Phase II clinical trial of pentoxyfilline (PTX), a known antifibrogenic antiinflammatory agent of proven safety in infants, is being conducted in infants with newly-diagnosed BA (registered with clinical trials.gov) to determine whether PTX has sufficient biological activity against BA, with minimal risk, which warrants further study. We hypothesize that PTX will be a safe and effective therapeutic agent to improve outcomes for select children with progressive biliary fibrosis/cirrhosis. Since there are currently no effective medical therapies for CHiLDREN diseases, proper exploration of the safety and efficacy of this agent would perfectly fit within the charge of ChiLDREN, which is uniquely poised to examine such novel therapies on a large scale. We hope to renew our productive contribution to achieving all the aims of ChiLDREN, helping to make a difference for children with liver diseases. We expect to provide high-value participation, capitalize on the well- developed ChiLDREN serum and tissue repository in the search for non-invasive biomarkers and better prediction of outcomes, embark upon fruitful mechanistic studies on the molecular pathogenesis of these diseases, and help lead investigations of novel safe therapies to help fill the current therapeutic void.