{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:35:55Z","timestamp":1787009755906,"version":"build-2736575974"},"reference-count":72,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T00:00:00Z","timestamp":1543968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CSA\/043\/2012"],"award-info":[{"award-number":["NMRC\/CSA\/043\/2012"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CSA(SI)\/008\/2016"],"award-info":[{"award-number":["NMRC\/CSA(SI)\/008\/2016"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["CIRG\/1459\/2016"],"award-info":[{"award-number":["CIRG\/1459\/2016"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/TA\/0003\/2012"],"award-info":[{"award-number":["NMRC\/TA\/0003\/2012"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CSA-INV\/ 0012\/2016"],"award-info":[{"award-number":["NMRC\/CSA-INV\/ 0012\/2016"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CSA(SI)\/008\/2016"],"award-info":[{"award-number":["NMRC\/CSA(SI)\/008\/2016"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010757","name":"National Centre for the Replacement Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/L001780\/1"],"award-info":[{"award-number":["NC\/L001780\/1"]}],"id":[{"id":"10.13039\/501100010757","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P026494\/1"],"award-info":[{"award-number":["MR\/P026494\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CSA\/007\/2009"],"award-info":[{"award-number":["NMRC\/CSA\/007\/2009"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CSA\/0059\/2014"],"award-info":[{"award-number":["NMRC\/CSA\/0059\/2014"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2019,3]]},"abstract":"ABSTRACT<\/jats:title>\n \n Adeno\u2010associated viral vectors (AAVs) achieve stable therapeutic expression without long\u2010term toxicity in adults with hemophilia. To avert irreversible complications in congenital disorders producing early pathogenesis, safety and efficacy of AAV\u2010intrauterine gene transfer (IUGT) requires assessment We therefore performed IUGT of AAV5 or \u20108 with liver\u2010specific promoter\u20101 encoding either human coagulation factors IX (hPIX) or \u00d7 (hFX) into\n Macaca fascicularis<\/jats:italic>\n fetuses at \u223c0.4 gestation. The initial cohort received 1 \u00d7 10\n 12<\/jats:sup>\n vector genomes (vgs) of AAV5\u2010hFIX (\n n<\/jats:italic>\n = 5; 0.45 \u00d7 10\n 13<\/jats:sup>\n vg\/kg birth weight), resulting in \u223c3.0% hPIX at birth and 0.6\u20136.8% over 19\u201351 mo. The next cohort received 0.2\u20101 \u00d7 10\n 13<\/jats:sup>\n vg boluses. AAV5\u2010hPX animals (\n n<\/jats:italic>\n = 3; 3.57 \u00d7 10\n 13<\/jats:sup>\n vg\/kg) expressed <1% at birth and 9.4\u201327.9% up to 42 mo. AAV8\u2010hFIX recipients (\n n<\/jats:italic>\n = 3; 2.56 \u00d7 10\n 13<\/jats:sup>\n vg\/kg) established 4.2\u201341.3% expression perinatally and 9.8\u201325.3% over 46 mo. Expression with AAV8\u2010hFX (\n n<\/jats:italic>\n = 6,3.12 \u00d7 10\n 13<\/jats:sup>\n vg\/kg) increased from <1% perinatally to 9.8\u201313.4% >35 mo. Low expressers (<1%,\n n<\/jats:italic>\n = 3) were postnatally challenged with 2 \u00d7 10\n 11<\/jats:sup>\n vg\/kg AAV5 resulting in 2.4\u201313.2% expression and demonstrating acquired tolerance. Linear amplification\u2010mediated\u2010PCR analysis demonstrated random integration of 57\u201388% of AAV sequences retrieved from hepatocytes with no events occurring in or near oncogenesis\u2010associated genes. Thus, early\u2010IUGT in macaques produces sustained curative expression related significantly to integrated AAV in the absence of clinical toxicity, supporting its therapeutic potential for early\u2010onset monogenic disorders.\u2014Chan, J. K. Y., Gil\u2010Farina I., Johana, N., Rosales, G., Tan, Y. W., Ceiler, J., Mcintosh, J., Ogden, B., Waddington, S. N., Schmidt, M., Biswas, A., Choolani, M., Nathwani, A. G., Mattar, C. N. Z. Therapeutic expression of human clotting factors IX and \u00d7 following adeno\u2010associated viral vector\u2010mediated intrauterine gene transfer in early\u2010gestation fetal macaques. FASEB J. 33, 3954\u20133967 (2019).\n www.fasebj.org<\/jats:ext-link>\n <\/jats:p>","DOI":"10.1096\/fj.201801391r","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T15:05:01Z","timestamp":1544022301000},"page":"3954-3967","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Therapeutic expression of human clotting factors IX and \u00d7 following adeno\u2010associated viral vector\u2010mediated intrauterine gene transfer in early\u2010gestation fetal macaques"],"prefix":"10.1096","volume":"33","author":[{"given":"Jerry K. Y.","family":"Chan","sequence":"first","affiliation":[{"name":"Reproductive Medicine KK Women's and Children's Hospital Singapore Singapore"},{"name":"Cancer and Stem Cell Biology Program Duke-National University of Singapore (NUS) Medical School Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Gil-Farina","sequence":"additional","affiliation":[{"name":"Department of Translational Oncology German Cancer Research Center National Center for Tumor Diseases Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuryanti","family":"Johana","sequence":"additional","affiliation":[{"name":"Reproductive Medicine KK Women's and Children's Hospital Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Rosales","sequence":"additional","affiliation":[{"name":"United College London (UCL) Cancer Institute University College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Wan","family":"Tan","sequence":"additional","affiliation":[{"name":"Reproductive Medicine KK Women's and Children's Hospital Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessika","family":"Ceiler","sequence":"additional","affiliation":[{"name":"Department of Translational Oncology German Cancer Research Center National Center for Tumor Diseases Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Mcintosh","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynaecology Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Ogden","sequence":"additional","affiliation":[{"name":"SingHealth Experimental Medicine Centre Singapore Health Services Pte Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon N.","family":"Waddington","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London London United Kingdom"},{"name":"Faculty of Health Sciences Wits\/South African Medical Research Council (SAMRC) Antiviral Gene Therapy Research Unit University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Schmidt","sequence":"additional","affiliation":[{"name":"United College London (UCL) Cancer Institute University College London London United Kingdom"},{"name":"GeneWerk Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arijit","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Translational Oncology German Cancer Research Center National Center for Tumor Diseases Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Choolani","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynaecology Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit C.","family":"Nathwani","sequence":"additional","affiliation":[{"name":"United College London (UCL) Cancer Institute University College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Citra N. Z.","family":"Mattar","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynaecology Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2017.06.011"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.26865"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708483"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708538"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407309"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2012.06.006"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(99)00083-3"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1054\/blre.2002.0191"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615219"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3233\/TRD-160005"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043039"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.09.001"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1657520"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","unstructured":"Morowati S. Ranjbar R. andYounesi M.(2015)Molecular analysis of patients with severe congenital factor \u00d7 deficiency: first report from north and northwest of Iran. [E-pub ahead of print].Hematology10.1179\/1607845415Y.0000000019","DOI":"10.1179\/1607845415Y.0000000019"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12511"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.11.008"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2011.148"},{"key":"e_1_2_8_20_1","first-page":"9","article-title":"Candidate diseases for prenatal gene therapy","volume":"891","author":"David A. L.","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.216"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.4134"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02723955"},{"key":"e_1_2_8_24_1","first-page":"55","volume-title":"Preterm Birth: Causes, Consequences, and Prevention","author":"Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes","year":"2007"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-533-0_9"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2008-0456"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1164"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-12-4837"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003454"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.107"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.2815"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300219"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2013.03.098"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.04.003"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2010.007"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-09-377630"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652309787909544"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566523054065039"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.9.4580-4590.2002"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01001-08"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-4310(00)01810-4"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-306647"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2011.00194"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.37.110801.143717"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-03-010181"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.15.6969-6976.2001"},{"key":"e_1_2_8_47_1","first-page":"1359","article-title":"In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor","volume":"101","author":"Waddington S. N.","year":"2003","journal-title":"Bbod"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.4155\/tde.11.17"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.009"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.015"},{"key":"e_1_2_8_51_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/978-1-61779-873-3_12","article-title":"Animal models for prenatal gene therapy: the nonhuman primate model","volume":"891","author":"Mattar C. N.","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2004.12.022"},{"key":"e_1_2_8_53_1","first-page":"1662","article-title":"Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques","volume":"100","author":"Nathwani A. C.","year":"2002","journal-title":"Bbod"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.81"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1103"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2011.219"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-0705.1991.01030162.x"},{"key":"e_1_2_8_58_1","first-page":"1022","article-title":"Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B","volume":"131","author":"Miesbach W.","year":"2018","journal-title":"Bbod"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2016.01.017"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.274"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033286"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.151"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.1.214-224.2005"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.8.3793-3803.2000"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.22.11343-11349.2002"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.3.7608"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12372"},{"key":"e_1_2_8_68_1","first-page":"2590","article-title":"Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice","volume":"119","author":"Merianos D. J.","year":"2009","journal-title":"J. Clin. Invest."},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44907"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79213"},{"key":"e_1_2_8_71_1","first-page":"2653","article-title":"Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver","volume":"107","author":"Nathwani A. C.","year":"2006","journal-title":"Bbod"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2003.09.001"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108046"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201801391R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201801391R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201801391R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:48:41Z","timestamp":1761673721000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201801391R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,5]]},"references-count":72,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,3]]}},"alternative-id":["10.1096\/fj.201801391R"],"URL":"https:\/\/doi.org\/10.1096\/fj.201801391r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,5]]},"assertion":[{"value":"2018-07-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}