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

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

Author information

1
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
2
Division of Metabolic Disease, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, USA.
3
1] Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [2] Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [3] Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [4] The Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [5] The Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
4
1] Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [2] Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [3] The Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [4] The Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [5] Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [6] Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA [7] Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Erratum in

Abstract

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.

PMID:
25474440
PMCID:
PMC4320015
DOI:
10.1038/gt.2014.106
[Indexed for MEDLINE]
Free PMC Article

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