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Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen-inducible arginase-1 deficient mouse model harboring a deletion of  Arg1  exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing the  C lustered,  R egularly  I nterspaced,  S hort  P alindromic  R epeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction with  piggyBac  technology to target and reincorporate exons 7 and 8 at the specific  Arg1  locus in attempts to restore the function of arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) and macrophages  in vitro . While successful gene targeted repair was achieved, minimal urea cycle function was observed in the targeted iHLCs compared to adult hepatocytes likely due to inadequate maturation of the cells. On the other hand, iPSC-derived macrophages expressed substantial amounts of “repaired” arginase. Our studies provide proof-of-concept for gene-editing at the  Arg1  locus and highlight the challenges that lie ahead to restore sufficient liver-based urea cycle function in patients with urea cycle disorders.

Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency