Strategies to rescue the consequences of inducible arginase-1 deficiency in mice.
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.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Laurel L
LL
Ballantyne
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Yuan Yan
YY
Sin
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Tim
T
St Amand
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Joshua
J
Si
Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent, Belgium; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Centre, Melbourne, Australia.
Steven
S
Goossens
Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent, Belgium; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Lieven
L
Haenebalcke
Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent, Belgium; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Centre, Melbourne, Australia.
Jody J
JJ
Haigh
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Lianna
L
Kyriakopoulou
Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Andreas
A
Schulze
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Colin D
CD
Funk
D000818:Animals; D001119:Arginase / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D018753:Diet, Protein-Restricted; D019587:Dietary Supplements; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D005804:Genes, Lethal; D017930:Genes, Reporter; D056426:Genetic Loci; D005822:Genetic Vectors / Q000235:genetics; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009952:Ornithine / Q000008:administration & dosage / Q000097:blood; D010641:Phenotype; D022661:RNA, Untranslated / Q000235:genetics; D014161:Transduction, Genetic; D019076:Transgenes
C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D022661:RNA, Untranslated; D009952:Ornithine; C544448:Arg1 protein, mouse; D001119:Arginase