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Here, we investigated the efficacy of liver\u2010specific GS overexpression for therapy of hyperammonemia. To achieve hepatic GS overexpression, we generated a helper\u2010dependent adenoviral (HDAd) vector expressing the murine GS under the control of a liver\u2010specific expression cassette (HDAd\u2010GS). Compared to mice injected with a control vector expressing an unrelated reporter gene (HDAd\u2010alpha\u2010fetoprotein), wild\u2010type mice with increased hepatic GS showed reduced blood ammonia levels and a concomitant increase of blood glutamine after intraperitoneal injections of ammonium chloride, whereas blood urea was unaffected. Moreover, injection of HDAd\u2010GS reduced blood ammonia levels at baseline and protected against acute hyperammonemia following ammonia challenge in a mouse model with conditional hepatic deficiency of carbamoyl phosphate synthetase 1 (\n                    <jats:italic>Cps1<\/jats:italic>\n                    ), the initial and rate\u2010limiting step of ureagenesis. In summary, we found that upregulation of hepatic GS reduced hyperammonemia in wild\u2010type and\n                    <jats:italic>Cps1<\/jats:italic>\n                    \u2010deficient mice, thus confirming a key role of GS in ammonia detoxification. These results suggest that hepatic GS augmentation therapy has potential for treatment of both primary and secondary forms of hyperammonemia.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12070","type":"journal-article","created":{"date-parts":[[2019,2,6]],"date-time":"2019-02-06T07:24:57Z","timestamp":1549437897000},"page":"1128-1135","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hepatic glutamine synthetase augmentation enhances ammonia detoxification"],"prefix":"10.1002","volume":"42","author":[{"given":"Leandro R.","family":"Soria","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine  Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Nitzahn","sequence":"additional","affiliation":[{"name":"Department of Surgery David Geffen School of Medicine at UCLA  Los Angeles California, USA"},{"name":"Molecular Biology Institute at 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