# A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system

## TL;DR

A new mouse model for CPS1 deficiency was created to study the effects of high ammonia levels on brain development and test potential treatments.

## Contribution

A novel hypomorphic murine model of CPS1 deficiency was developed to study hyperammonemia's effects on the nervous system.

## Key findings

- The hypomorphic model shows elevated ammonia and glutamate levels and reduced citrulline.
- The model biochemically phenocopies human CPS1 deficiency with impaired ureagenesis.
- The model is 100% penetrant and reproducible, providing a platform for therapeutic development.

## Abstract

Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that, in neonatal onset, is typically characterized by severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 h of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with dysfunction of Cps1 that could be detected biochemically. Characterization, based on the orthologous human variant Asn674Ile, revealed that the variant is reproducible, 100% penetrant and biochemically phenocopies the human disorder. The hypomorph presents with elevated ammonia and glutamate, and reduced citrulline, and with an impaired rate of ureagenesis, providing a novel platform to study and develop therapies for CPS1 deficiency.

Summary: A hypomorphic mouse model of carbamoyl phosphate synthetase 1 deficiency was developed, allowing assessment of the effects of mild hyperammonemia on development, with potential use in new therapeutic advancements.