Advancing our Understanding of Rare Pediatric Liver Diseases

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PROJECT SUMMARY This proposal is in response to a request for applications for the Continuation of ChiLDReN, the Childhood Liver Disease Research Network. Over the past fifteen years, through a coordinated effort, investigations of eight cholestatic pediatric disorders have been advanced and we have established a robust database and biorepository for further research. Little is known about the pathogenesis, natural history, and optimal treatment strategies for the rare pediatric liver diseases investigated by ChiLDReN. We at The Children's Hospital of Philadelphia (CHOP) propose to continue to participate in this Consortium, and thereby advance the field through collaborative research. Only through collaboration can we improve the quality and efficiency of care provided to all individuals diagnosed with one of the diseases studied by this network. CHOP has been a highly productive member of ChiLDReN for the last 15 years. In this application, we propose to continue our participation in all aspects of the ChiLDReN consortium, including clinical trials, observational and interventional study protocols, genomics initiatives, dissemination of research findings and ancillary studies. In addition, we have included a proposal for validation of candidate genes and proteins identified through Network Genomics and Biomarker studies through two Aims. 1) We propose to develop control and disease-specific tissue microarrays (TMA) for high throughput analysis of protein localization; 2) We propose to investigate the function of candidate genes in a zebrafish model. Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by bile duct paucity and cholestasis along with manifestations in other organ systems. Many ALGS patients have profound cholestasis, with significantly elevated bilirubin and bile acids, development of xanthomas and severe pruritus that has a major impact on quality of life. Despite the debilitating effects of pruritus on many aspects of daily life, including school and sleep, there are few effective medical therapies. Patients who continue to experience intractable pruritus despite treatment with all available therapies may require surgical intervention such as biliary diversion, or even liver transplantation in the most refractory cases. Therefore, there is a critical unmet need for safe and effective medical therapies for the cholestasis of pruritus in ALGS and other disorders. We propose to conduct a randomized, double-blind crossover study of sertraline for the treatment of pruritus in Alagille syndrome. Outcome measures will assess changes in pruritus, sleep, quality of life and autotaxin activity after treatment with active drug or placebo. Safety and tolerability will also be assessed. Successful completion of this study will determine the efficacy of sertraline as a therapy for pruritus in ALGS and potentially identify sleep variables that could be used as objective study endpoints in this population. We anticipate that this work will contribute new knowledge regarding the treatment of pruritus in cholestatic patients.