{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:15:42Z","timestamp":1792653342570,"version":"4.5.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T00:00:00Z","timestamp":1583712000000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["5 R01 NS100979"],"award-info":[{"award-number":["5 R01 NS100979"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Systemically administered lipid nanoparticles (LNPs) targeting the liver were able to express the cytoplasmic enzyme arginase 1 (ARG1) in a conditional knockout model of ARG1 deficiency. Metabolically, this resulted in maintaining normal plasma ammonia and arginine, preventing the build-up of excessive hepatic arginine, and obviated the development of guanidino compounds, a hallmark of this enzyme deficiency. Unlike controls, repeat dosing of LNPs encapsulating human codon-optimized\n                    <jats:italic>ARG1<\/jats:italic>\n                    messenger RNA led to long-term survival without evidence of toxicity, restoration of ureagenesis, and the ability to handle toxic ammonia loading. These findings have implications for therapy of ARG1 deficiency, which is presently inadequately treated and leads to progressive neurological decline.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1906182116","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T20:29:16Z","timestamp":1568060956000},"page":"21150-21159","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":145,"title":["Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency"],"prefix":"10.1073","volume":"116","author":[{"given":"Brian","family":"Truong","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Allegri","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children\u2019s Research Center, University Children\u2019s Hospital, 8032 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine E.","family":"Burke","sequence":"additional","affiliation":[{"name":"Moderna, Inc., Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuling","family":"Zhu","sequence":"additional","affiliation":[{"name":"Moderna, Inc., Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Cederbaum","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children\u2019s Research Center, University Children\u2019s Hospital, 8032 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo G. V.","family":"Martini","sequence":"additional","affiliation":[{"name":"Moderna, Inc., Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald S.","family":"Lipshutz","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;"},{"name":"Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,9,9]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.07.008"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2003.10.012"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00210403"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2012.03.016"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2010.01.012"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(85)90120-2"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.153.197"},{"key":"e_1_3_3_8_2","first-page":"61","article-title":"Excretion of guanidino-derivates in urine of hyperargininemic patients","volume":"24","author":"Wiechert P.","year":"1976","unstructured":"P. Wiechert ., Excretion of guanidino-derivates in urine of hyperargininemic patients. J. Genet. Hum. 24, 61\u201372 (1976).","journal-title":"J. Genet. Hum."},{"key":"e_1_3_3_9_2","first-page":"101","article-title":"Hyperargininemia, epilepsy and the metabolism of guanidino compounds","volume":"28","author":"Wiechert P.","year":"1989","unstructured":"P. Wiechert, B. Marescau, P. P. De Deyn, A. Lowenthal, Hyperargininemia, epilepsy and the metabolism of guanidino compounds. Padiatr. Grenzgeb. 28, 101\u2013106 (1989).","journal-title":"Padiatr. Grenzgeb."},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.09.016"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv352"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1013960712516"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2013_218"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.13.4491-4498.2002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.65"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.129"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2014.99"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.23.13324"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-018-07643-z"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302375"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0897-16.2016"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2012.99"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79213"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.1496"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1073"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.72"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(02)00338-6"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0676.2002.01702.x"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1619653114"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.08.049"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1733"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S106625"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.06.020"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1159\/000059843"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12488"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2017.03.016"},{"key":"e_1_3_3_38_2","volume-title":"GeneReviews","author":"Ah Mew N.","year":"2003","unstructured":"N. Ah Mew ., \u201cUrea cycle disorders overview\u201d in GeneReviews, M. P. Adam ., Eds. (University of Washington, Seattle, 2003)."},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.06.003"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-8-64"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2014.106"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.04.005"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.06.053"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2004.04.006"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.11.081"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.04.001"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-459-3_17"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2016.11.038"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1906182116","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1906182116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T04:40:45Z","timestamp":1649824845000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1906182116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,9]]},"references-count":48,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2019,10,15]]}},"alternative-id":["10.1073\/pnas.1906182116"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1906182116","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,9]]},"assertion":[{"value":"2019-09-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}