Strategies to rescue the consequences of inducible arginase-1 deficiency in mice
- Author
- Laurel L Ballantyne, Yuan Yan Sin, Tim St Amand, Joshua Si, Steven Goossens (UGent) , Lieven Haenebalcke (UGent) , Jody Haigh (UGent) , Lianna Kyriakopoulou, Andrea Schulze and Colin D Funk
- Organization
- 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
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-6888023
- 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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