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Strategies to rescue the consequences of inducible arginase-1 deficiency in mice

(2015) PLOS ONE. 10(5).
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Abstract
Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken beta-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies.
Keywords
EXPRESSION, HYPERARGININEMIA, MOUSE, GENE-THERAPY, UREA CYCLE DISORDERS, MUTATIONS, PHENOTYPE, VECTORS, MODEL

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Citation

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MLA
Ballantyne, Laurel L., et al. “Strategies to Rescue the Consequences of Inducible Arginase-1 Deficiency in Mice.” PLOS ONE, vol. 10, no. 5, 2015, doi:10.1371/journal.pone.0125967.
APA
Ballantyne, L. L., Sin, Y. Y., St Amand, T., Si, J., Goossens, S., Haenebalcke, L., … Funk, C. D. (2015). Strategies to rescue the consequences of inducible arginase-1 deficiency in mice. PLOS ONE, 10(5). https://doi.org/10.1371/journal.pone.0125967
Chicago author-date
Ballantyne, Laurel L, Yuan Yan Sin, Tim St Amand, Joshua Si, Steven Goossens, Lieven Haenebalcke, Jody Haigh, Lianna Kyriakopoulou, Andrea Schulze, and Colin D Funk. 2015. “Strategies to Rescue the Consequences of Inducible Arginase-1 Deficiency in Mice.” PLOS ONE 10 (5). https://doi.org/10.1371/journal.pone.0125967.
Chicago author-date (all authors)
Ballantyne, Laurel L, Yuan Yan Sin, Tim St Amand, Joshua Si, Steven Goossens, Lieven Haenebalcke, Jody Haigh, Lianna Kyriakopoulou, Andrea Schulze, and Colin D Funk. 2015. “Strategies to Rescue the Consequences of Inducible Arginase-1 Deficiency in Mice.” PLOS ONE 10 (5). doi:10.1371/journal.pone.0125967.
Vancouver
1.
Ballantyne LL, Sin YY, St Amand T, Si J, Goossens S, Haenebalcke L, et al. Strategies to rescue the consequences of inducible arginase-1 deficiency in mice. PLOS ONE. 2015;10(5).
IEEE
[1]
L. L. Ballantyne et al., “Strategies to rescue the consequences of inducible arginase-1 deficiency in mice,” PLOS ONE, vol. 10, no. 5, 2015.
@article{6888023,
  abstract     = {{Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken beta-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies.}},
  articleno    = {{e0125967}},
  author       = {{Ballantyne, Laurel L and Sin, Yuan Yan and St Amand, Tim and Si, Joshua and Goossens, Steven and Haenebalcke, Lieven and Haigh, Jody and Kyriakopoulou, Lianna and Schulze, Andrea and Funk, Colin D}},
  issn         = {{1932-6203}},
  journal      = {{PLOS ONE}},
  keywords     = {{EXPRESSION,HYPERARGININEMIA,MOUSE,GENE-THERAPY,UREA CYCLE DISORDERS,MUTATIONS,PHENOTYPE,VECTORS,MODEL}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{20}},
  title        = {{Strategies to rescue the consequences of inducible arginase-1 deficiency in mice}},
  url          = {{http://doi.org/10.1371/journal.pone.0125967}},
  volume       = {{10}},
  year         = {{2015}},
}

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