{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T07:21:57Z","timestamp":1781594517178,"version":"3.54.5"},"reference-count":72,"publisher":"SAGE Publications","issue":"9-10","license":[{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>\n                    Adeno-associated virus (AAV) vectors are proving to be clinically transformative tools in the treatment of monogenic genetic disease. Rapid ongoing development of this technology promises to not only increase the number of monogenic disorders amenable to this approach but also to bring diseases with complex multigenic and nongenetic etiologies within therapeutic reach. In this study, we explore the broader paradigm of converting the liver into a biofactory for systemic output of therapeutic molecules using AAV-mediated delivery of the endonuclease DNaseI as an exemplar. DNaseI can clear neutrophil extracellular traps (NETs), which are nuclear-protein structures possessing antimicrobial action, also involved in the pathophysiology of clinically troubling immune-mediated diseases. However, a translational challenge is short half-life of the enzyme\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    (&lt;5\u2009h). This study demonstrates that AAV-mediated liver-targeted gene transfer stably induces serum DNaseI activity to &gt;190-fold above physiological levels. In lupus-prone mice (NZBWF1), the activity was maintained for longer than 6 months, the latest time point tested, and resulted in a clear functional effect with reduced renal presence of neutrophils, NETs, IgG, and complement C3. However, treatment in this complex disease model did not extend lifespan, improve serological endpoints, or preserve renal function, indicating there are elements of pathophysiology not accessible to DNaseI in the NZBWF1 model. We conclude that a translational solution to the challenge of short half-life of DNaseI is AAV-mediated gene delivery and that this may be efficacious in treating disease where NETs are a dominant pathological mechanism.\n                  <\/jats:p>","DOI":"10.1089\/hum.2021.264","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T06:29:31Z","timestamp":1647412171000},"page":"560-571","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Conversion of the Liver into a Biofactory for DNaseI Using Adeno-Associated Virus Vector Gene Transfer Reduces Neutrophil Extracellular Traps in a Model of Systemic Lupus Erythematosus"],"prefix":"10.1177","volume":"33","author":[{"given":"Amina","family":"Ahmad","sequence":"first","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mawj","family":"Mandwie","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim M.","family":"O'Sullivan","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Smyth","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrod","family":"York","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Doyle","sequence":"additional","affiliation":[{"name":"Pathology, Sydney Children's Hospitals Network, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Holdsworth","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria"},{"name":"Department of Nephrology, Monash Health, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Pickering","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Disease, Imperial College London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Lachmann","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, New South Wales, Australia"},{"name":"Department of Discipline of Child and Adolescent Health, University of Sydney, Westmead, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9365-342X","authenticated-orcid":false,"given":"Grant J.","family":"Logan","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.12.007"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0802315"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31868-8"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0185-5"},{"issue":"1","key":"e_1_3_6_6_2","first-page":"604","article-title":"Spk-8011: preliminary results from a phase 1\/2 dose escalation trial of an investigational AAV-mediated gene therapy for hemophilia a","volume":"130","author":"George LA","year":"2017","unstructured":"George LA, , Ragni MV, , Samelson-Jones BJ, et al. Spk-8011: preliminary results from a phase 1\/2 dose escalation trial of an investigational AAV-mediated gene therapy for hemophilia a. Blood, 2017; 130(Suppl 1):604.","journal-title":"Blood"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407309"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708538"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108046"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12875"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.09.021"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba3312"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.05.004"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2021.022"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4657"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-021-00239-9"},{"key":"e_1_3_6_18_2","doi-asserted-by":"crossref","unstructured":"Lazarus RA Wagener JS. Recombinant human deoxyribonuclease I in pharmaceutical biotechnology: fundamentals and applications. In: Crommelin DJA Sindelar RD Meibohm B eds. Cham: Springer International Publishing 2019:471\u2013488.","DOI":"10.1007\/978-3-030-00710-2_22"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom10071036"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.2165\/00063030-200519030-00001"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04544.x"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00381.2014"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36198-2"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.316389"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1993.10"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11037"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.01.035"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12787"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1191\/0961203303lu357xx"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1996.d01-839.x"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.71.12.4742"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-10-4035"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.72"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182412299"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.3.2224-2232.1998"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2012.67"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3893"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.202"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-198303000-00002"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2016-000199"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2015.08.003"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2847"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00137"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909927107"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100450"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001180"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001201"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102404"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/91070"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/76032"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201847875"},{"key":"e_1_3_6_53_2","first-page":"447","article-title":"The relationship of desoxyribonuclease inhibitor levels in human sera to the occurrence of antinuclear antibodies","volume":"3","author":"Frost PG","year":"1968","unstructured":"Frost PG, , Lachmann PJ. The relationship of desoxyribonuclease inhibitor levels in human sera to the occurrence of antinuclear antibodies. Clin Exp Immunol, 1968; 3:447\u2013455.","journal-title":"Clin Exp Immunol"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00541153"},{"key":"e_1_3_6_55_2","first-page":"56","article-title":"Antinucleosome antibodies and decreased deoxyribonuclease activity in sera of patients with systemic lupus erythematosus","volume":"12","author":"Sallai K","year":"2005","unstructured":"Sallai K, , Nagy E, , Derfalvy B, et al. Antinucleosome antibodies and decreased deoxyribonuclease activity in sera of patients with systemic lupus erythematosus. Clin Diagn Lab Immunol, 2005; 12:56\u201359.","journal-title":"Clin Diagn Lab Immunol"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1177\/0961203308098189"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2012-0521"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012096"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.99"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1191\/096120398678920037"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar1936"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8091325"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67390"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.605930"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201138"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.034"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.975"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.38010"},{"key":"e_1_3_6_69_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.29.18374"},{"key":"e_1_3_6_70_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.19.11701"},{"key":"e_1_3_6_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.2439"},{"key":"e_1_3_6_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03770-2"},{"key":"e_1_3_6_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.06.017"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2021.264","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2021.264","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2021.264","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:56:31Z","timestamp":1777449391000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2021.264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5]]},"references-count":72,"journal-issue":{"issue":"9-10","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1089\/hum.2021.264"],"URL":"https:\/\/doi.org\/10.1089\/hum.2021.264","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5]]}}}