A liver-humanized mouse model of carbamoyl phosphate synthetase 1-deficiency.

DOI
Publisher DOI
PubMed ID
30843237
Abstract
A liver-humanized mouse model for CPS1-deficiency was generated by the high-level repopulation of the mouse liver with CPS1-deficient human hepatocytes. When compared with mice that are highly repopulated with CPS1-proficient human hepatocytes, mice that are repopulated with CPS1-deficient human hepatocytes exhibited characteristic symptoms of human CPS1 deficiency including an 80% reduction in CPS1 metabolic activity, delayed clearance of an ammonium chloride infusion, elevated glutamine and glutamate levels, and impaired metabolism of [15 N]ammonium chloride into urea, with no other obvious phenotypic differences. Because most metabolic liver diseases result from mutations that alter critical pathways in hepatocytes, a model that incorporates actual disease-affected, mutant human hepatocytes is useful for the investigation of the molecular, biochemical, and phenotypic differences induced by that mutation. The model is also expected to be useful for investigations of modified RNA, gene, and cellular and small molecule therapies for CPS1-deficiency. Liver-humanized models for this and other monogenic liver diseases afford the ability to assess the therapy on actual disease-affected human hepatocytes, in vivo, for long periods of time and will provide data that are highly relevant for investigations of the safety and efficacy of gene-editing technologies directed to human hepatocytes and the translation of gene-editing technology to the clinic.
Date Issued
2019-11
Publication Type
Article
Subject(s)
Subjects
CPS1-deficiency liver-humanized mice urea cycle defects
Language(s)
en
Author(s)
Srinivasan, Raghuraman C
Zabulica, Mihaela
Hammarstedt, Christina
Wu, Tingting
Gramignoli, Roberto
Kannisto, Kristina
Ellis, Ewa
Karadagi, Ahmad
Fingerhut, Ralph
Allegri, Gabriella
Rüfenacht, Véronique
Thöny, Beat
Häberle, Johannes
Strom, Stephen C
Additional Credits
Journal
Journal of inherited metabolic diseases
Publisher
Wiley
ISSN
0141-8955
Access(Rights)
open.access
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