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

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; Nuoffer, Jean-Marc; Strom, Stephen C (2019). A liver-humanized mouse model of carbamoyl phosphate synthetase 1-deficiency. Journal of inherited metabolic diseases, 42(6), pp. 1054-1063. Wiley 10.1002/jimd.12067

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Nuoffer, Jean-Marc

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0141-8955

Publisher:

Wiley

Language:

English

Submitter:

Alexandra Müller

Date Deposited:

30 Dec 2019 14:36

Last Modified:

13 Mar 2021 12:53

Publisher DOI:

10.1002/jimd.12067

PubMed ID:

30843237

Uncontrolled Keywords:

CPS1-deficiency liver-humanized mice urea cycle defects

BORIS DOI:

10.7892/boris.136890

URI:

https://boris.unibe.ch/id/eprint/136890

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