{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:10:04Z","timestamp":1792635004177,"version":"4.5.0"},"reference-count":66,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"708","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,8,9]]},"abstract":"<jats:p>\n                    Gene therapy for kidney diseases has proven challenging. Adeno-associated virus (AAV) is used as a vector for gene therapy targeting other organs, with particular success demonstrated in monogenic diseases. We aimed to establish gene therapy for the kidney by targeting a monogenic disease of the kidney podocyte. The most common cause of childhood genetic nephrotic syndrome is mutations in the podocyte gene\n                    <jats:italic>NPHS2<\/jats:italic>\n                    , encoding podocin. We used AAV-based gene therapy to rescue this genetic defect in human and mouse models of disease. In vitro transduction studies identified the AAV-LK03 serotype as a highly efficient transducer of human podocytes. AAV-LK03\u2013mediated transduction of podocin in mutant human podocytes resulted in functional rescue in vitro, and AAV 2\/9\u2013mediated gene transfer in both the inducible podocin knockout and knock-in mouse models resulted in successful amelioration of kidney disease. A prophylactic approach of AAV 2\/9 gene transfer before induction of disease in conditional knockout mice demonstrated improvements in albuminuria, plasma creatinine, plasma urea, plasma cholesterol, histological changes, and long-term survival. A therapeutic approach of AAV 2\/9 gene transfer 2 weeks after disease induction in proteinuric conditional knock-in mice demonstrated improvement in urinary albuminuria at days 42 and 56 after disease induction, with corresponding improvements in plasma albumin. Therefore, we have demonstrated successful AAV-mediated gene rescue in a monogenic renal disease and established the podocyte as a tractable target for gene therapy approaches.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abc8226","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T13:58:40Z","timestamp":1691589520000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":71,"title":["Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9537-9783","authenticated-orcid":true,"given":"Wen Y.","family":"Ding","sequence":"first","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeryia","family":"Kuzmuk","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."},{"name":"Purespring Therapeutics, Rolling Stock Yard, 188 York Way, London N7 9AS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7586-9945","authenticated-orcid":true,"given":"Sarah","family":"Hunter","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-634X","authenticated-orcid":true,"given":"Abigail","family":"Lay","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6340-0966","authenticated-orcid":true,"given":"Bryony","family":"Hayes","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9619-4636","authenticated-orcid":true,"given":"Matthew","family":"Beesley","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Cheltenham General Hospital, Cheltenham GL53 7AN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5834-6360","authenticated-orcid":true,"given":"Ruth","family":"Rollason","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-7306","authenticated-orcid":true,"given":"Jennifer A.","family":"Hurcombe","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-7712","authenticated-orcid":true,"given":"Fern","family":"Barrington","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrin","family":"Masson","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Cathery","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5836-3950","authenticated-orcid":true,"given":"Carl","family":"May","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8405-2948","authenticated-orcid":true,"given":"Jack","family":"Tuffin","sequence":"additional","affiliation":[{"name":"Purespring Therapeutics, Rolling Stock Yard, 188 York Way, London N7 9AS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6680-4816","authenticated-orcid":true,"given":"Timothy","family":"Roberts","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4685-5736","authenticated-orcid":true,"given":"Geraldine","family":"Mollet","sequence":"additional","affiliation":[{"name":"Laboratoire des Maladies R\u00e9nales H\u00e9r\u00e9ditaires, Inserm UMR 1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, Paris 75015, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2088-8310","authenticated-orcid":true,"given":"Colin J.","family":"Chu","sequence":"additional","affiliation":[{"name":"Academic Unit of Ophthalmology, Bristol Medical School, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4115-7867","authenticated-orcid":true,"given":"Jenny","family":"McIntosh","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, Paul O\u2019Gorman Building, University College London, London WC1E 6BT, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6183-2546","authenticated-orcid":true,"given":"Richard J.","family":"Coward","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9934-4940","authenticated-orcid":true,"given":"Corinne","family":"Antignac","sequence":"additional","affiliation":[{"name":"Laboratoire des Maladies R\u00e9nales H\u00e9r\u00e9ditaires, Inserm UMR 1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9, Paris 75015, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Nathwani","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, Paul O\u2019Gorman Building, University College London, London WC1E 6BT, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin I.","family":"Welsh","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9808-4518","authenticated-orcid":true,"given":"Moin A.","family":"Saleem","sequence":"additional","affiliation":[{"name":"Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108046"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2119913"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2113708"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1414221"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407309"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.76"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.108"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2014.35"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2014.14"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000057858.45649.F7"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.71"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.126"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.08.006"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11321-7"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018040426"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.krcp.2012.04.323"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.10.013"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014050489"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.06260614"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22485"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-018-3937-z"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45693"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc0800582"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/74166"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200112849"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1159\/000101789"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1600-0854.2003.00148.x"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009040379"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186574"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2000.279.6.F1027"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2016.12.006"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2005.12.018"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302698"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62117-0"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4149"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.27"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12875"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.1.309-319.1998"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2010.075"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.40"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017020143"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04193-w"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018070729"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005010055"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.098"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2477"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008070709"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008070795"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011040388"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90601.2008"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.274"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2017.07.004"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-269092"},{"key":"e_1_3_2_56_2","first-page":"2306","article-title":"Evaluation of a new tool for exploring podocyte biology: Mouse Nphs1 5\u2019 flanking region drives LacZ expression in podocytes","volume":"11","author":"Eremina V.","year":"2002","unstructured":"V.\u00a0Eremina, M. A.\u00a0Wong, S.\u00a0Cui, L.\u00a0Schwartz, S. E.\u00a0Quaggin, Evaluation of a new tool for exploring podocyte biology: Mouse Nphs1 5\u2019 flanking region drives LacZ expression in podocytes. J. Am. Soc. Nephrol. 11, 2306\u20132314 (2002).","journal-title":"J. Am. Soc. Nephrol."},{"key":"e_1_3_2_57_2","first-page":"442","article-title":"Adeno-associated virus vector integration","volume":"11","author":"Deyle D. R.","year":"2009","unstructured":"D. R.\u00a0Deyle, D. W.\u00a0Russell, Adeno-associated virus vector integration. Curr. Opin. Mol. Ther. 11, 442\u2013447 (2009).","journal-title":"Curr. Opin. Mol. Ther."},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-101416-041936"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3300938"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005050547"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V133630"},{"key":"e_1_3_2_62_2","first-page":"525","article-title":"Podocyte culture: Tricks of the trade","volume":"17","author":"Ni L.","year":"2012","unstructured":"L.\u00a0Ni, M.\u00a0Saleem, P. W.\u00a0Mathieson, Podocyte culture: Tricks of the trade. Nephrol. Ther. 17, 525\u2013531 (2012).","journal-title":"Nephrol. Ther."},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08235-1"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5000277"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-009-0882-y"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1318"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abc8226","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T12:50:43Z","timestamp":1705409443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abc8226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,9]]},"references-count":66,"journal-issue":{"issue":"708","published-print":{"date-parts":[[2023,8,9]]}},"alternative-id":["10.1126\/scitranslmed.abc8226"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abc8226","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,9]]},"assertion":[{"value":"2020-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eabc8226"}}