The Liver Center at Texas Children's Hospital/Baylor College of Medicine (TCH/BCM) has been an active participant in BARC and CLiC, and is excited by the opportunity to continue participation. The overarching aims of this Center are to help advance the clinical, research, and educational goals of the ChiLDREN grant.
Aim 1 : Continued Clinical Center participation in all aspects of ChiLDREN. This Center has participated in all BARC &CLiC programs since 2005, as well as the CF Liver Disease Consortium.
We Aim to continue our participation, which has provided high levels of enrollment into BARC (POO3, P004, POO5) and CLiC. The clinical infrastructure is broadly supportive, and the personnel experienced, which, along with centralized care and research, allows this Center a high level of enrollment and longitudinal follow-up. We will also engage in all aspects of observational and interventional trials in ChiLDREN.
Aim 2 : Explore the genetic determinants of adaptation to pediatric liver disease. Among the unique aspects that determine outcomes of liver disease in infants and children, is the contribution of the individual's genetic makeup, best exemplified by the short timelines that underlie whether these children will adapt well or not. We hypothesize that by detailed, broad-based, unbiased exploration of individual patient genomic determinants (e.g., whole exome sequencing or focused studies of nuclear receptor pathways), we will be able to assign genetic categorization of children into those able to adapt well, and those who do not. Moreover, we expect this information to allow for targeted therapeutic discoveries.
Aim 3 : Design and initiate Phase 1 and 2 clinical trials exploring Nor-UDCA as a therapeutic agent in a variety of cholestatic and fibrosing liver diseases in children. Nor-ursodeoxycholic acid (Nor-UDCA), a side chain modification of UDCA, is currently undergoing Phase 1 trials in Europe for cholestatic liver diseases in adults. Nor-UDCA enhances bile flow, perhaps through cholehepatic shunting. We hypothesize that Nor- UDCA will be a safe and effective therapeutic agent for select children with cholestatic liver disease;specifically those with ABCB4 disease, as well as children with BA &CFLD who have evidence of biliary fibrosis/cirrhosis or portal hypertension. Since there are currently no effective medical therapies for cholestasis, proper exploration of the safety and efficacy of this investigational agent would perfectly fit within the charge of ChiLDREN, and, arguably, is the only Consortium that could test such potential therapeutics. Relevance: With ongoing involvement of this Center, we hope to be able to contribute to the achievement of all the goals of ChiLDREN, arguably the main means to make a difference for children with cholestatic liver diseases. This CC's participation expects to provide continued high enrollment, embark upon novel studies on genetic determinants in a broad-based approach, and finally, help develop investigations of a new anti-cholestatic and anti-fibrotic therapeutic, to help fill the current therapeutic void.
|Russo, Pierre; Magee, John C; Anders, Robert A et al. (2016) Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome: A Multicenter Study. Am J Surg Pathol 40:1601-1615|
|Shneider, Benjamin L; Magee, John C; Karpen, Saul J et al. (2016) Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia. J Pediatr 170:211-7.e1-2|
|Ye, Wen; Rosenthal, Philip; Magee, John C et al. (2015) Factors Determining ?-Bilirubin Levels in Infants With Biliary Atresia. J Pediatr Gastroenterol Nutr 60:659-63|
|Teckman, Jeffrey H; Rosenthal, Philip; Abel, Robert et al. (2015) Baseline Analysis of a Young ?-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension. J Pediatr Gastroenterol Nutr 61:94-101|
|Kamath, Binita M; Chen, Zhen; Romero, Rene et al. (2015) Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome. J Pediatr 167:390-6.e3|
|Bezerra, Jorge A; Spino, Cathie; Magee, John C et al. (2014) Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA 311:1750-9|
|Ng, Vicky Lee; Haber, Barbara H; Magee, John C et al. (2014) Medical status of 219 children with biliary atresia surviving long-term with their native livers: results from a North American multicenter consortium. J Pediatr 165:539-546.e2|
|Venkat, Veena L; Shneider, Benjamin L; Magee, John C et al. (2014) Total serum bilirubin predicts fat-soluble vitamin deficiency better than serum bile acids in infants with biliary atresia. J Pediatr Gastroenterol Nutr 59:702-7|
|Sundaram, Shikha S; Alonso, Estella M; Haber, Barbara et al. (2013) Health related quality of life in patients with biliary atresia surviving with their native liver. J Pediatr 163:1052-7.e2|
|Schwarz, Kathleen B; Haber, Barbara H; Rosenthal, Philip et al. (2013) Extrahepatic anomalies in infants with biliary atresia: results of a large prospective North American multicenter study. Hepatology 58:1724-31|
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