Minimal ureagenesis is necessary for survival in the murine model of hyperargininemia treated by AAV-based gene therapy

Gene Ther. 2015 Feb;22(2):111-5. doi: 10.1038/gt.2014.106. Epub 2014 Dec 4.


Hyperammonemia is less severe in arginase 1 deficiency compared with other urea cycle defects. Affected patients manifest hyperargininemia and infrequent episodes of hyperammonemia. Patients typically suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation, seizures and intellectual disability; death is less common than with other urea cycle disorders. In a mouse model of arginase I deficiency, the onset of symptoms begins with weight loss and gait instability, which progresses toward development of tail tremor with seizure-like activity; death typically occurs at about 2 weeks of life. Adeno-associated viral vector gene replacement strategies result in long-term survival of mice with this disorder. With neonatal administration of vector, the viral copy number in the liver greatly declines with hepatocyte proliferation in the first 5 weeks of life. Although the animals do survive, it is not known from a functional standpoint how well the urea cycle is functioning in the adult animals that receive adeno-associated virus. In these studies, we administered [1-13C] acetate to both littermate controls and adeno-associated virus-treated arginase 1 knockout animals and examined flux through the urea cycle. Circulating ammonia levels were mildly elevated in treated animals. Arginine and glutamine also had perturbations. Assessment 30 min after acetate administration demonstrated that ureagenesis was present in the treated knockout liver at levels as low at 3.3% of control animals. These studies demonstrate that only minimal levels of hepatic arginase activity are necessary for survival and ureagenesis in arginase-deficient mice and that this level of activity results in control of circulating ammonia. These results may have implications for potential therapy in humans with arginase deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonia / blood
  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Genetic Therapy
  • Hyperammonemia / blood
  • Hyperammonemia / genetics
  • Hyperammonemia / therapy
  • Hyperargininemia / blood
  • Hyperargininemia / genetics
  • Hyperargininemia / therapy*
  • Liver / enzymology
  • Liver / pathology
  • Mice
  • Mice, Knockout


  • Ammonia
  • Arg1 protein, mouse
  • Arginase