Develop a human liver system to study SLC25A13 mutations in citrin deficiency

项目总结

PROJECT SUMMARY Citrin deficiency (CD), an autosomal recessive disorder caused by mutations in SLC25A13 gene, is a pan-ethnic rare disease. Currently there is no specific drug for CD. Dietary management is regarded as the most effective treatment for CD, as well as a decisive factor in the clinical outcome of patients. However, dietary management has only been based on small case reports and dietary management for children with CD is generally poor, especially in areas where carbohydrate-based diets are predominant. Thus, further research is needed to understand disease pathogenesis and facilitate more specific therapeutic development. CD manifests as age-dependent phenotypes and can have severe clinical outcome including failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and citrullinemia type 2 (CTLN2) with a sudden development of hyperammonemic encephalopathy, as well as other clinical manifestations. However, the mechanisms by which how SLC25A13 loss-of-function leads to the abovementioned disease phenotypes remain largely unclear. It also remains poorly understood how the age of onset and incomplete penetrance seen in CD patients are determined. A major unmet need in the study of CD is the lack of a reliable human-relevant model that mimics the entire spectrum of this disease in humans. So far, the only available models to study CD are the knockout (KO) mice (i.e., Slc25a13-KO and Slc25a13 and Gpd2-double KO). Owing to marked species-specific differences in gene regulation especially in glycolysis, the utility and clinical relevance of these models are debated. The need for human-relevant system is further underscored by the observations showing variable age of onset and incomplete penetrance seen in CTLN2 patients where additional environmental and/or genetic triggers are suspected. The primary research goal of this application is to leverage a human induced pluripotent stem cell (iPSC)- derived multicellular in vitro liver model developed in our laboratory to create a human-relevant model for studying SLC25A13 in CD. Across the two specific aims, we plan to generate liver cultures harboring wild-type or SLC25A13 KO cells and to characterize the possible disease phenotypes that are relevant to human CD. Developing an iPSC-derived renewable and genetically manipulatable human system for the study of SLC25A13 in CD will facilitate the detailed dissection of disease pathogenesis. Moreover, given the lack of suitable human- relevant systems to study CD, our iPSC-derived platform will provide an urgently needed new platform to test interventions and promote the development of specific therapeutics. Finally, this initial support will allow us to perform pilot analysis and characterization and to acquire critical preliminary data for a bigger grant application that will facilitate these efforts.