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

Ballantyne, L. L., Sin, Y. Y., St. Amand, T., Si, J., Goossens, S., Haenebalcke, L., Haigh, J. J., Kyriakopoulou, L., Schulze, A. and Funk, C. D. (2015) Strategies to rescue the consequences of inducible arginase-1 deficiency in mice. PLoS ONE, 10(5), e0125967. (doi: 10.1371/journal.pone.0125967) (PMID:25938595) (PMCID:PMC4418594)

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 β-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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sin, Dr Angie
• Authors: Ballantyne, L. L., Sin, Y. Y., St. Amand, T., Si, J., Goossens, S., Haenebalcke, L., Haigh, J. J., Kyriakopoulou, L., Schulze, A., and Funk, C. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2015 Ballantyne et al.
• First Published: First published in PLoS ONE 10(5): e0125967
• Publisher Policy: Reproduced under a Creative Commons License