Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency

Lindsay C. Burrage, Qin Sun, Sarah H. Elsea, Ming Ming Jiang, Sandesh C S Nagamani, Arthur E. Frankel, Everett Stone, Susan E. Alters, Dale E. Johnson, Scott W. Rowlinson, George Georgiou, Brendan H. Lee

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 frompatients 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.

Original languageEnglish (US)
Pages (from-to)6417-6427
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number22
DOIs
StatePublished - 2015

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Hyperargininemia
Arginase
Arginine
Enzymes
Hyperammonemia
Inborn Urea Cycle Disorder
Therapeutics
Ornithine
Macaca fascicularis
Reducing Agents
Cerebral Palsy
Natural History
Intellectual Disability

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Burrage, L. C., Sun, Q., Elsea, S. H., Jiang, M. M., Nagamani, S. C. S., Frankel, A. E., ... Lee, B. H. (2015). Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Human Molecular Genetics, 24(22), 6417-6427. https://doi.org/10.1093/hmg/ddv352

Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. / Burrage, Lindsay C.; Sun, Qin; Elsea, Sarah H.; Jiang, Ming Ming; Nagamani, Sandesh C S; Frankel, Arthur E.; Stone, Everett; Alters, Susan E.; Johnson, Dale E.; Rowlinson, Scott W.; Georgiou, George; Lee, Brendan H.

In: Human Molecular Genetics, Vol. 24, No. 22, 2015, p. 6417-6427.

Research output: Contribution to journalArticle

Burrage, LC, Sun, Q, Elsea, SH, Jiang, MM, Nagamani, SCS, Frankel, AE, Stone, E, Alters, SE, Johnson, DE, Rowlinson, SW, Georgiou, G & Lee, BH 2015, 'Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency', Human Molecular Genetics, vol. 24, no. 22, pp. 6417-6427. https://doi.org/10.1093/hmg/ddv352
Burrage, Lindsay C. ; Sun, Qin ; Elsea, Sarah H. ; Jiang, Ming Ming ; Nagamani, Sandesh C S ; Frankel, Arthur E. ; Stone, Everett ; Alters, Susan E. ; Johnson, Dale E. ; Rowlinson, Scott W. ; Georgiou, George ; Lee, Brendan H. / Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 22. pp. 6417-6427.
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