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Mol Ther. 2014 Oct;22(10):1792-802. doi: 10.1038/mt.2014.99. Epub 2014 Jun 3.

Myocyte-mediated arginase expression controls hyperargininemia but not hyperammonemia in arginase-deficient mice.

Author information

1
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
2
1] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [2] Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
3
Department of Biochemistry, University of Washington, Seattle, Washington, USA.
4
1] Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [2] Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [3] Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [4] The Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [5] The Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
5
1] Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [2] Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [3] The Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [4] The Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [5] Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [6] Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA [7] Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Abstract

Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia that cause neurological impairment and growth retardation. We previously developed a neonatal mouse adeno-associated viral vector (AAV) rh10-mediated therapeutic approach with arginase expressed by a chicken β-actin promoter that controlled plasma ammonia and arginine, but hepatic arginase declined rapidly. This study tested a codon-optimized arginase cDNA and compared the chicken β-actin promoter to liver- and muscle-specific promoters. ARG1(-/-) mice treated with AAVrh10 carrying the liver-specific promoter also exhibited long-term survival and declining hepatic arginase accompanied by the loss of AAV episomes during subsequent liver growth. Although arginase expression in striated muscle was not expected to counteract hyperammonemia, due to muscle's lack of other urea cycle enzymes, we hypothesized that the postmitotic phenotype in muscle would allow vector genomes to persist, and hence contribute to decreased plasma arginine. As anticipated, ARG1(-/-) neonatal mice treated with AAVrh10 carrying a modified creatine kinase-based muscle-specific promoter did not survive longer than controls; however, their plasma arginine levels remained normal when animals were hyperammonemic. These data imply that plasma arginine can be controlled in arginase deficiency by muscle-specific expression, thus suggesting an alternative approach to utilizing the liver for treating hyperargininemia.

PMID:
24888478
PMCID:
PMC4428413
DOI:
10.1038/mt.2014.99
[Indexed for MEDLINE]
Free PMC Article

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