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

Year: 2015

Type: article

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.

Source: Human Molecular Genetics

DOI: 10.1093/hmg/ddv352

Authors: 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, Brendan H. Lee

Institutions: Baylor College of Medicine, Texas Children's Hospital, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, The University of Texas at Austin, Aegera Therapeutics (Canada)

Language: English

Topic: Metabolism and Genetic Disorders

Subfield: Clinical Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Doris Duke Charitable Foundation, ACMG Foundation for Genetic and Genomic Medicine, Rare Diseases Clinical Research Network, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development

OpenAlex ID: W1885058798