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Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (<jats:italic>Otc<\/jats:italic><jats:sup><jats:italic>spf\u2010ash<\/jats:italic><\/jats:sup>) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: <jats:italic>Gls2<\/jats:italic>) or glutamate dehydrogenase 1 (GLUD1, gene name: <jats:italic>Glud1<\/jats:italic>) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of <jats:italic>Gls2<\/jats:italic> but not <jats:italic>Glud1<\/jats:italic> by AAV8\u2010mediated delivery of a short hairpin RNA in <jats:italic>Otc<\/jats:italic><jats:sup><jats:italic>spf\u2010ash<\/jats:italic><\/jats:sup> mice diminished hyperammonemia and reduced lethality. Knockdown of <jats:italic>Gls2<\/jats:italic> but not <jats:italic>Glud1<\/jats:italic> in <jats:italic>Otc<\/jats:italic><jats:sup><jats:italic>spf\u2010ash<\/jats:italic><\/jats:sup> mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that <jats:italic>Gls2<\/jats:italic> hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.<\/jats:p>","DOI":"10.1002\/jimd.12474","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T08:09:57Z","timestamp":1641456597000},"page":"470-480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model"],"prefix":"10.1002","volume":"45","author":[{"given":"Xia","family":"Mao","sequence":"first","affiliation":[{"name":"Regeneron Pharmaceuticals  Tarrytown New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Chen","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals  Tarrytown New York 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