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.

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations

“…Later, the effects of pegylated human recombinant ARG1 in a phase 2 clinical trial for liver cancer (https://clinicaltrials.gov/ct2/show/NCT02089763) (Tsui et al., ) were evaluated. This opened the way to the testing of this same pegylated enzyme to treat ARGD, first in a mouse model (Burrage et al., ) and then in patients, in a current phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT02488044).…”

Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

“…The purpose of the present studies was to establish a screening approach to identify alternative UTRs with improved expression relative to a reference UTR [7] to improve the stability of arginase I (ARG1) mRNA in multiple cell types. ARG1 deficiency represents a rare genetic disease whereby loss of the ARG1 gene leads to disease pathology and replacement of the ARG1 protein may have clinical benefit [11], therefore, use of ARG1 mRNA open reading frame (ORF) may have clinical utility. Using a UTR combinatorial library two 5′ UTRs were identified, complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1), which improved ARG1 protein expression.…”

Arginase I mRNA therapy – a novel approach to rescue arginase 1 enzyme deficiency

“…Current Standard of Care (SOC) for patients with ARG1 deficiency is diet control. Nitrogen scavenger drugs such as phenyl butyrate, a low-protein diet or ornithine supplementation give symptomatic relief by reduction in arginine levels [4], but fail to prevent neuro-cognitive deficits [5,6]. A protein deficient diet is provided to children with ARG1 deficiency, which in turn results in slow growth and delayed/missed developmental milestones [7,8].…”

“…However, it had no effect in the liver thus failing to rescue the lethal mouse Arg1 knockout (KO) phenotype. In addition, enzyme replacement therapy failed to rescue hyperargininemia [4,9]. An attempt at gene therapy with Shope papilloma virus, to induce virallyencoded arginase was also unsuccessful [16].…”