{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:20:50Z","timestamp":1784164850167,"version":"3.55.0"},"reference-count":50,"publisher":"Elsevier BV","issue":"7","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T00:00:00Z","timestamp":1625702400000},"content-version":"vor","delay-in-days":372,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Therapy"],"published-print":{"date-parts":[[2020,7]]},"DOI":"10.1016\/j.ymthe.2020.04.011","type":"journal-article","created":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T21:44:32Z","timestamp":1587073472000},"page":"1717-1730","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":16,"title":["Split AAV-Mediated Gene Therapy Restores Ureagenesis in a Murine Model of Carbamoyl Phosphate Synthetase 1 Deficiency"],"prefix":"10.1016","volume":"28","author":[{"given":"Matthew","family":"Nitzahn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Allegri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhail","family":"Khoja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Truong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Makris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald S.","family":"Lipshutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ymthe.2020.04.011_bib1","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/S0021-9258(17)33785-7","article-title":"A major polypeptide component of rat liver mitochondria: carbamyl phosphate synthetase","volume":"251","author":"Clarke","year":"1976","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.ymthe.2020.04.011_bib2","first-page":"E34","article-title":"Sources and Fates of Carbamyl Phosphate: A Labile Energy-Rich Molecule with Multiple Facets","volume":"7","author":"Shi","year":"2018","journal-title":"Biology (Basel)"},{"key":"10.1016\/j.ymthe.2020.04.011_bib3","doi-asserted-by":"crossref","unstructured":"Summar, M.L., Koelker, S., Freedenberg, D., Le Mons, C., Haberle, J., Lee, H.S., and Kirmse, B.; European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). Electronic address: http:\/\/www.e-imd.org\/en\/index.phtml; Members of the Urea Cycle Disorders Consortium (UCDC). Electronic address: http:\/\/rarediseasesnetwork.epi.usf.edu\/ucdc\/ (2013). The incidence of urea cycle disorders. Mol. Genet. Metab. 110, 179\u2013180.","DOI":"10.1016\/j.ymgme.2013.07.008"},{"key":"10.1016\/j.ymthe.2020.04.011_bib4","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13023-017-0661-x","article-title":"Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland","volume":"12","author":"Nettesheim","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"10.1016\/j.ymthe.2020.04.011_bib5","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1080\/14728222.2017.1294685","article-title":"Targeting CPS1 in the treatment of Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea cycle disorder","volume":"21","author":"Diez-Fernandez","year":"2017","journal-title":"Expert Opin. Ther. Targets"},{"key":"10.1016\/j.ymthe.2020.04.011_bib6","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ymgme.2011.10.020","article-title":"Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome","volume":"105","author":"Wang","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymthe.2020.04.011_bib7","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1038\/mt.2013.139","article-title":"Adeno-associated virus-mediated rescue of neonatal lethality in argininosuccinate synthetase-deficient mice","volume":"21","author":"Kok","year":"2013","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib8","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1038\/s41467-018-05972-1","article-title":"Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer","volume":"9","author":"Baruteau","year":"2018","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ymthe.2020.04.011_bib9","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1038\/mt.2012.129","article-title":"Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy","volume":"20","author":"Lee","year":"2012","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib10","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/hep.510290112","article-title":"Mice deficient in the urea-cycle enzyme, carbamoyl phosphate synthetase I, die during the early neonatal period from hyperammonemia","volume":"29","author":"Schofield","year":"1999","journal-title":"Hepatology"},{"key":"10.1016\/j.ymthe.2020.04.011_bib11","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ymgme.2007.08.123","article-title":"Contrasting features of urea cycle disorders in human patients and knockout mouse models","volume":"93","author":"Deignan","year":"2008","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymthe.2020.04.011_bib12","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1002\/jimd.12067","article-title":"A liver-humanized mouse model of carbamoyl phosphate synthetase 1-deficiency","volume":"42","author":"Srinivasan","year":"2019","journal-title":"J.\u00a0Inherit. Metab. Dis."},{"key":"10.1016\/j.ymthe.2020.04.011_bib13","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1073\/pnas.85.1.160","article-title":"Distribution of glutamine synthetase and carbamoyl-phosphate synthetase I in vertebrate liver","volume":"85","author":"Smith","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.ymthe.2020.04.011_bib14","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1177\/33.12.4067274","article-title":"Development of the heterogeneous distribution of carbamoyl-phosphate synthetase (ammonia) in rat-liver parenchyma during postnatal development","volume":"33","author":"Gaasbeek Janzen","year":"1985","journal-title":"J.\u00a0Histochem. Cytochem."},{"key":"10.1016\/j.ymthe.2020.04.011_bib15","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/nature13864","article-title":"Promoterless gene targeting without nucleases ameliorates haemophilia B in mice","volume":"517","author":"Barzel","year":"2015","journal-title":"Nature"},{"key":"10.1016\/j.ymthe.2020.04.011_bib16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1089\/10430340460732445","article-title":"Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates","volume":"15","author":"Brunetti-Pierri","year":"2004","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib17","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2174\/15665232113136660006","article-title":"Biosafety challenges for use of lentiviral vectors in gene therapy","volume":"13","author":"Rothe","year":"2013","journal-title":"Curr. Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib18","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1038\/sj.gt.3302231","article-title":"Silencing of episomal transgene expression by plasmid bacterial DNA elements in\u00a0vivo","volume":"11","author":"Chen","year":"2004","journal-title":"Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib19","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/75087","article-title":"Overcoming adeno-associated virus vector size limitation through viral DNA heterodimerization","volume":"6","author":"Sun","year":"2000","journal-title":"Nat. Med."},{"key":"10.1016\/j.ymthe.2020.04.011_bib20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1006\/mthe.2001.0456","article-title":"Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison","volume":"4","author":"Duan","year":"2001","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib21","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/sj.mt.6300322","article-title":"A hybrid vector system expands adeno-associated viral vector packaging capacity in a transgene-independent manner","volume":"16","author":"Ghosh","year":"2008","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib22","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ymthe.2017.11.019","article-title":"Triple Vectors Expand AAV Transfer Capacity in the Retina","volume":"26","author":"Maddalena","year":"2018","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib23","doi-asserted-by":"crossref","first-page":"e39233","DOI":"10.1371\/journal.pone.0039233","article-title":"Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer","volume":"7","author":"Grose","year":"2012","journal-title":"PLoS ONE"},{"key":"10.1016\/j.ymthe.2020.04.011_bib24","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/acn3.172","article-title":"AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models","volume":"2","author":"Sondergaard","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"10.1016\/j.ymthe.2020.04.011_bib25","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.ymthe.2017.12.019","article-title":"Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression","volume":"26","author":"Vidal","year":"2018","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib26","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ymgme.2018.04.001","article-title":"Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy","volume":"124","author":"Khoja","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymthe.2020.04.011_bib27","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1089\/hum.2019.132","article-title":"Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease","volume":"30","author":"Dyka","year":"2019","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib28","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0887-8994(00)00259-9","article-title":"Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy","volume":"24","author":"Takeoka","year":"2001","journal-title":"Pediatr. Neurol."},{"key":"10.1016\/j.ymthe.2020.04.011_bib29","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1002\/humu.21406","article-title":"Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations","volume":"32","author":"H\u00e4berle","year":"2011","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ymthe.2020.04.011_bib30","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1002\/lt.22407","article-title":"Late-onset carbamoyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation","volume":"17","author":"Bates","year":"2011","journal-title":"Liver Transpl."},{"key":"10.1016\/j.ymthe.2020.04.011_bib31","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.3748\/wjg.v21.i13.4063","article-title":"Urea cycle disorders: a case report of a successful treatment with liver transplant and a literature review","volume":"21","author":"Foschi","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"10.1016\/j.ymthe.2020.04.011_bib32","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ymgme.2016.12.002","article-title":"Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes","volume":"120","author":"Shi","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"10.1016\/j.ymthe.2020.04.011_bib33","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1089\/hum.2019.053","article-title":"Insights into Gene Therapy for Urea Cycle Defects by Mathematical Modeling","volume":"30","author":"Kok","year":"2019","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib34","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1002\/jimd.12048","article-title":"A constitutive knockout of murine carbamoyl phosphate synthetase 1 results in death with marked hyperglutaminemia and hyperammonemia","volume":"42","author":"Khoja","year":"2019","journal-title":"J.\u00a0Inherit. Metab. Dis."},{"key":"10.1016\/j.ymthe.2020.04.011_bib35","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1002\/emmm.201302948","article-title":"Effective delivery of large genes to the retina by dual AAV vectors","volume":"6","author":"Trapani","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.ymthe.2020.04.011_bib36","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/gt.2014.8","article-title":"Efficient gene delivery to the cone-enriched pig retina by dual AAV vectors","volume":"21","author":"Colella","year":"2014","journal-title":"Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/mt.2009.258","article-title":"Characterization of genome integrity for oversized recombinant AAV vector","volume":"18","author":"Dong","year":"2010","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib38","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/mt.2009.255","article-title":"Effect of genome size on AAV vector packaging","volume":"18","author":"Wu","year":"2010","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib39","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1089\/hgtb.2012.090","article-title":"Limitations of encapsidation of recombinant self-complementary adeno-associated viral genomes in different serotype capsids and their quantitation","volume":"23","author":"Wang","year":"2012","journal-title":"Hum. Gene Ther. Methods"},{"key":"10.1016\/j.ymthe.2020.04.011_bib40","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/sj.gt.3302262","article-title":"Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice","volume":"11","author":"Mochizuki","year":"2004","journal-title":"Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0022-1759(84)90046-2","article-title":"Determination of blood volume in the mouse with 51chromium-labelled erythrocytes","volume":"73","author":"Sluiter","year":"1984","journal-title":"J.\u00a0Immunol. Methods"},{"key":"10.1016\/j.ymthe.2020.04.011_bib42","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1182\/blood-2002-09-2889","article-title":"Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway","volume":"102","author":"Davidoff","year":"2003","journal-title":"Blood"},{"key":"10.1016\/j.ymthe.2020.04.011_bib43","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1038\/mt.2009.139","article-title":"Sexually dimorphic patterns of episomal rAAV genome persistence in the adult mouse liver and correlation with hepatocellular proliferation","volume":"17","author":"Dane","year":"2009","journal-title":"Mol. Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib44","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1089\/hum.2011.238","article-title":"In\u00a0vivo gene transfer strategies to achieve partial correction of von Willebrand disease","volume":"23","author":"Wang","year":"2012","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib45","doi-asserted-by":"crossref","first-page":"e9396","DOI":"10.15252\/emmm.201809396","article-title":"A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice","volume":"11","author":"Al-Moyed","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.ymthe.2020.04.011_bib46","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1089\/hum.2018.015","article-title":"Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN","volume":"29","author":"Hinderer","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.ymthe.2020.04.011_bib47","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nbt0702-697","article-title":"Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene","volume":"20","author":"Halbert","year":"2002","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.ymthe.2020.04.011_bib48","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1203\/00006450-199704000-00012","article-title":"Adenovirus-mediated in\u00a0vivo gene transfer rapidly protects ornithine transcarbamylase-deficient mice from an ammonium challenge","volume":"41","author":"Ye","year":"1997","journal-title":"Pediatr. Res."},{"key":"10.1016\/j.ymthe.2020.04.011_bib49","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.cca.2016.11.038","article-title":"A simple dried blood spot-method for in\u00a0vivo measurement of ureagenesis by gas chromatography-mass spectrometry using stable isotopes","volume":"464","author":"Allegri","year":"2017","journal-title":"Clin. Chim. Acta"},{"key":"10.1016\/j.ymthe.2020.04.011_bib50","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1002\/humu.22349","article-title":"Molecular characterization of carbamoyl-phosphate synthetase (CPS1) deficiency using human recombinant CPS1 as a key tool","volume":"34","author":"Diez-Fernandez","year":"2013","journal-title":"Hum. Mutat."}],"container-title":["Molecular Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1525001620301921?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1525001620301921?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T17:56:22Z","timestamp":1761501382000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1525001620301921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7]]},"references-count":50,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,7]]}},"alternative-id":["S1525001620301921"],"URL":"https:\/\/doi.org\/10.1016\/j.ymthe.2020.04.011","relation":{},"ISSN":["1525-0016"],"issn-type":[{"value":"1525-0016","type":"print"}],"subject":[],"published":{"date-parts":[[2020,7]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Split AAV-Mediated Gene Therapy Restores Ureagenesis in a Murine Model of Carbamoyl Phosphate Synthetase 1 Deficiency","name":"articletitle","label":"Article Title"},{"value":"Molecular Therapy","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ymthe.2020.04.011","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2020 The American Society of Gene and Cell Therapy.","name":"copyright","label":"Copyright"}]}}