Targeting CPS1 in the treatment of Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea cycle disorder

Expert Opin Ther Targets. 2017 Apr;21(4):391-399. doi: 10.1080/14728222.2017.1294685. Epub 2017 Feb 20.


Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder (UCD), which can lead to life-threatening hyperammonemia. Unless promptly treated, it can result in encephalopathy, coma and death, or intellectual disability in surviving patients. Over recent decades, therapies for CPS1D have barely improved leaving the management of these patients largely unchanged. Additionally, in many cases, current management (protein-restriction and supplementation with citrulline and/or arginine and ammonia scavengers) is insufficient for achieving metabolic stability, highlighting the importance of developing alternative therapeutic approaches. Areas covered: After describing UCDs and CPS1D, we give an overview of the structure- function of CPS1. We then describe current management and potential novel treatments including N-carbamoyl-L-glutamate (NCG), pharmacological chaperones, and gene therapy to treat hyperammonemia. Expert opinion: Probably, the first novel CPS1D therapies to reach the clinics will be the already commercial substance NCG, which is the standard treatment for N-acetylglutamate synthase deficiency and has been proven to rescue specific CPS1D mutations. Pharmacological chaperones and gene therapy are under development too, but these two technologies still have key challenges to be overcome. In addition, current experimental therapies will hopefully add further treatment options.

Keywords: N-carbamoyl-L-glutamate; Urea cycle disorders; carbamoyl phosphate synthetase 1; flavonoids; gene therapy; pharmacological chaperones.

Publication types

  • Review

MeSH terms

  • Animals
  • Carbamoyl-Phosphate Synthase (Ammonia) / genetics
  • Carbamoyl-Phosphate Synthase (Ammonia) / metabolism*
  • Carbamoyl-Phosphate Synthase I Deficiency Disease / genetics
  • Carbamoyl-Phosphate Synthase I Deficiency Disease / physiopathology
  • Carbamoyl-Phosphate Synthase I Deficiency Disease / therapy*
  • Genetic Therapy / methods
  • Glutamates / therapeutic use*
  • Humans
  • Molecular Chaperones / pharmacology
  • Mutation
  • Urea Cycle Disorders, Inborn / physiopathology
  • Urea Cycle Disorders, Inborn / therapy


  • Glutamates
  • Molecular Chaperones
  • N-carbamylglutamate
  • Carbamoyl-Phosphate Synthase (Ammonia)