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We present the results of studies in a neonatal bovine model of citrullinemia, an inborn error of urea-cycle metabolism characterized by deficiency of argininosuccinate synthetase and consequent life-threatening hyperammonemia. Measurements of the flux of nitrogen from orally administered\n                    <jats:sup>15<\/jats:sup>\n                    NH\n                    <jats:sub>4<\/jats:sub>\n                    to [\n                    <jats:sup>15<\/jats:sup>\n                    N]urea were used to determine urea-cycle activity\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In control animals, these isotopic measurements proved to be unaffected by pharmacologic treatments. Systemic administration of a first-generation\n                    <jats:italic>E1<\/jats:italic>\n                    -deleted adenoviral vector expressing human argininosuccinate synthetase resulted in transduction of hepatocytes and partial correction of the enzyme defect. The isotopic method showed significant restoration of urea synthesis. Moreover, the calves showed clinical improvement and normalization of plasma glutamine levels after treatment. The results show the clinical efficacy of treating a large-animal model of an inborn error of hepatocyte metabolism in conjunction with a method for sensitively measuring correction\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These studies will be applicable to human trials of the treatment of this disorder and other related urea-cycle disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.96.7.3981","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:39:15Z","timestamp":1027679955000},"page":"3981-3986","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":42,"title":["Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia"],"prefix":"10.1073","volume":"96","author":[{"given":"Brendan","family":"Lee","sequence":"first","affiliation":[{"name":"Departments of Molecular and Human Genetics, and Pediatrics, and U.S. Department of Agriculture\/Agriculture Research Service Children\u2019s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030; The Howard Hughes Medical Institute, Houston, TX 77030; and The Elizabeth Macarthur Agricultural Institute, New South Wales Agriculture, Menangle NSW 2568, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Human Genetics, and Pediatrics, and U.S. Department of Agriculture\/Agriculture Research Service Children\u2019s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030; The Howard Hughes Medical Institute, Houston, TX 77030; and The Elizabeth Macarthur Agricultural Institute, New South Wales Agriculture, Menangle NSW 2568, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Healy","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Human Genetics, and Pediatrics, and U.S. Department of Agriculture\/Agriculture Research Service Children\u2019s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030; The Howard Hughes Medical Institute, Houston, TX 77030; and The Elizabeth 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