ArticleMolecular genetics and metabolism2018
Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy.
Article in Molecular genetics and metabolism, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system.Disease models & mechanisms · 2025Article
- IMPC impact on preclinical mouse models.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control.Molecular therapy. Nucleic acids · 2025Article
- Hepatic Gene Expression of Angiogenic and Regeneration Markers in Cats with Congenital Portosystemic Shunts (CPSS).Veterinary sciences · 2024Article
- Intermittent lipid nanoparticle mRNA administration prevents cortical dysmyelination associated with arginase deficiency.Molecular therapy. Nucleic acids · 2022Article
- Gene therapy for guanidinoacetate methyltransferase deficiency restores cerebral and myocardial creatine while resolving behavioral abnormalities.Molecular therapy. Methods & clinical development · 2022Article
- Gene therapy approaches for equine osteoarthritis.Frontiers in veterinary science · 2022Review
- Liver-humanized mice: A translational strategy to study metabolic disorders.Journal of cellular physiology · 2022Review
- CRISPR-Mediated Genomic Addition to CPS1 Deficient iPSCs is Insufficient to Restore Nitrogen Homeostasis.The Yale journal of biology and medicine · 2021Article
- CPS1: Looking at an ancient enzyme in a modern light.Molecular genetics and metabolism · 2020Review
- Split AAV-Mediated Gene Therapy Restores Ureagenesis in a Murine Model of Carbamoyl Phosphate Synthetase 1 Deficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy.International journal of molecular sciences · 2020Review
- A constitutive knockout of murine carbamoyl phosphate synthetase 1 results in death with marked hyperglutaminemia and hyperammonemia.Journal of inherited metabolic disease · 2019Article
- Hepatic glutamine synthetase augmentation enhances ammonia detoxification.Journal of inherited metabolic disease · 2019Article
- Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
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11 authors.
Funding
Abstract
Carbamoyl phosphate synthetase 1 (CPS1) is a urea cycle enzyme that forms carbamoyl phosphate from bicarbonate, ammonia and ATP. Bi-allelic mutations of the CPS1 gene result in a urea cycle disorder presenting with hyperammonemia, often with reduced citrulline, and without orotic aciduria. CPS1 deficiency is particularly challenging to treat and lack of early recognition typically results in early neonatal death. Therapeutic interventions have limited efficacy and most patients develop long-term neurologic sequelae. Using transgenic techniques, we generated a conditional Cps1 knockout mouse. By loxP/Cre recombinase technology, deletion of the Cps1 locus was achieved in adult transgenic animals using a Cre recombinase-expressing adeno-associated viral vector. Within four weeks from vector injection, all animals developed hyperammonemia without orotic aciduria and died. Minimal CPS1 protein was detectable in livers. To investigate the efficacy of gene therapy for CPS deficiency following knock-down of hepatic endogenous CPS1 expression, we injected these mice with a helper-dependent adenoviral vector (HDAd) expressing the large murine CPS1 cDNA under control of the phosphoenolpyruvate carboxykinase promoter. Liver-directed HDAd-mediated gene therapy resulted in survival, normalization of plasma ammonia and glutamine, and 13% of normal Cps1 expression. A gender difference in survival suggests that female mice may require higher hepatic CPS1 expression. We conclude that this conditional murine model recapitulates the clinical and biochemical phenotype detected in human patients with CPS1 deficiency and will be useful to investigate ammonia-mediated neurotoxicity and for the development of cell- and gene-based therapeutic approaches.
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