{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T22:58:18Z","timestamp":1789945098521,"version":"4.0.1"},"reference-count":37,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2014,11,24]],"date-time":"2014-11-24T00:00:00Z","timestamp":1416787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2014,11,24]],"date-time":"2014-11-24T00:00:00Z","timestamp":1416787200000},"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":[[2015,2]]},"abstract":"<jats:p>\n                    Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (&lt;10%) empty capsid and have performed comprehensive dose\u2013response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2\u2013500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =20) and hemophilic mice (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    =60 animals). With respect to the role of empty capsids, we demonstrated that\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice 8\u201310 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity, 100\u2013500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1\/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335).\n                  <\/jats:p>","DOI":"10.1089\/hum.2014.106","type":"journal-article","created":{"date-parts":[[2014,11,24]],"date-time":"2014-11-24T16:40:37Z","timestamp":1416847237000},"page":"69-81","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":99,"title":["Employing a Gain-of-Function Factor IX Variant R338L to Advance the Efficacy and Safety of Hemophilia B Human Gene Therapy: Preclinical Evaluation Supporting an Ongoing Adeno-Associated Virus Clinical Trial"],"prefix":"10.1177","volume":"26","author":[{"given":"Paul E.","family":"Monahan","sequence":"first","affiliation":[{"name":"University of North Carolina"},{"name":"University of North Carolina"},{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjiang","family":"Sun","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Gui","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genlin","family":"Hu","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Hannah","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Wichlan","sequence":"additional","affiliation":[{"name":"University of North Carolina"},{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Wu","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Grieger","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengwen","family":"Li","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thipparat","family":"Suwanmanee","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrel W.","family":"Stafford","sequence":"additional","affiliation":[{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen J.","family":"Booth","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jade J.","family":"Samulski","sequence":"additional","affiliation":[{"name":"Asklepios BioPharmaceutical"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Kafri","sequence":"additional","affiliation":[{"name":"University of North Carolina"},{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott W.J.","family":"McPhee","sequence":"additional","affiliation":[{"name":"Asklepios BioPharmaceutical"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Jude","family":"Samulski","sequence":"additional","affiliation":[{"name":"University of North Carolina"},{"name":"University of North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2014,11,24]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.272"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1358"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-306647"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-03-010181"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02220.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300355"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108046"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2010.202"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.20.12089"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904377"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-08-2990"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2008.084"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-432591"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-440123"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.188"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-10-4035"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386509-0.00012-0"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V90.10.3962"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03545.x"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2008.01689.x"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-01-131417"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.170"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.90"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1107\/S1744309112045563"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904514106"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12101"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2006.01348.x"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005795"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2014.045"},{"key":"e_1_3_3_31_2","first-page":"364","article-title":"Turning severe into moderate haemophilia by prophylaxis: are we reaching our goal?","volume":"11","author":"den Uijl I","year":"2013","unstructured":"den Uijl I, , Biesma D, , Grobbee D, et al. Turning severe into moderate haemophilia by prophylaxis: are we reaching our goal?. 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