Abstract
Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While individually rare, there is a large number of other genetic-based liver diseases. The approach described here could be applied to a broad range and a large number of patients with these hepatic diseases where it could serve as an in vitro model, as well as identify successful strategies for corrective cell-based therapy.
Highlights
Liver is an organ performing a diverse repertoire of metabolic processes, including ammonia metabolism and urea production through the urea cycle
Due to low OTCD incidence, primary hepatocytes are frequently not available; a surrogate model was generated with induced pluripotent stem cells (iPSC)
The hypothesis tested was that the iPSC which contain the rare mutation and hepatic defect could be employed to identify successful editing procedures, and when the edited or unedited cells were successfully differentiated into organoid hepatocyte-like cells (HLC), a difference in the phenotype could be identified
Summary
Liver is an organ performing a diverse repertoire of metabolic processes, including ammonia metabolism and urea production through the urea cycle. Mutations in any of the genes encoding the six enzymes or two mitochondrial transporters that constitute the urea cycle could lead to urea cycle disorders (UCD). In the case of UCD, excess nitrogen (in the form of ammonia) accumulates in the body and may result in irreversible neurological and intellectual impairment, growth retardation and hyperammonemic episodes, which can prove fatal if not rapidly corrected [1]. The most common UCD is ornithine transcarbamylase (OTC) deficiency (OTCD), which affects 1 in 56,000 individuals [2]. Criteria for diagnosis of OTCD affected patients have been established and include elevated ammonia levels and detection of mutations in the OTC gene, decreased enzyme activity in the liver or family history of the disorder along with elevated urinary orotate
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
