title: Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency.
abstract: Arginase deficiency is caused by deficiency of arginase 1 (ARG1), a urea cycle enzyme that converts arginine to ornithine. Clinical features of arginase deficiency include elevated plasma arginine levels, spastic diplegia, intellectual disability, seizures and growth deficiency. Unlike other urea cycle disorders, recurrent hyperammonemia is typically less severe in this disorder. Normalization of plasma arginine levels is the consensus treatment goal, because elevations of arginine and its metabolites are suspected to contribute to the neurologic features. Using data from patients enrolled in a natural history study conducted by the Urea Cycle Disorders Consortium, we found that 97% of plasma arginine levels in subjects with arginase deficiency were above the normal range despite conventional treatment. Recently, arginine-degrading enzymes have been used to deplete arginine as a therapeutic strategy in cancer. We tested whether one of these enzymes, a pegylated human recombinant arginase 1 (AEB1102), reduces plasma arginine in murine models of arginase deficiency. In neonatal and adult mice with arginase deficiency, AEB1102 reduced the plasma arginine after single and repeated doses. However, survival did not improve likely, because this pegylated enzyme does not enter hepatocytes and does not improve hyperammonemia that accounts for lethality. Although murine models required dosing every 48 h, studies in cynomolgus monkeys indicate that less frequent dosing may be possible in patients. Given that elevated plasma arginine rather than hyperammonemia is the major treatment challenge, we propose that AEB1102 may have therapeutic potential as an arginine-reducing agent in patients with arginase deficiency.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Burrage
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.affiliation: Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA and.
authors.forename: Everett
authors.initials: E
authors.lastname: Stone
authors.affiliation: Aeglea BioTherapeutics, Austin, TX 78746, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Alters
authors.affiliation: Aeglea BioTherapeutics, Austin, TX 78746, USA.
authors.forename: Dale E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Aeglea BioTherapeutics, Austin, TX 78746, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Rowlinson
authors.affiliation: Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA and.
authors.forename: George
authors.initials: G
authors.lastname: Georgiou
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Texas Children's Hospital, Houston, TX 77030, USA, blee@bcm.edu.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001119:Arginase / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*; D001120:Arginine / Q000097:blood* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000378:metabolism; D020162:Hyperargininemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008137:Longitudinal Studies; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use; D012640:Seizures / Q000097:blood / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D001120:Arginine; D001119:Arginase