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J Inherit Metab Dis. 2019 Nov;42(6):1054-1063. doi: 10.1002/jimd.12067. Epub 2019 Apr 2.

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

Author information

1
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
2
Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden.
3
Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
4
Division of Metabolism and Children's Research Centre (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
5
Swiss Newborn Screening Laboratory, University Children's Hospital Zurich, Zurich, Switzerland.
6
Zurich Centre for Integrative Human Physiology (ZIHP) and, Neuroscience Centre Zurich (ZNZ), Zurich, Switzerland.
7
Institute for Clinical Chemistry and University Children's Hospital, Bern, Switzerland.

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.

KEYWORDS:

CPS1-deficiency; liver-humanized mice; urea cycle defects

PMID:
30843237
DOI:
10.1002/jimd.12067

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