{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:54:26Z","timestamp":1782485666737,"version":"3.54.5"},"reference-count":25,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T00:00:00Z","timestamp":1506038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HHSN268201300001C"],"award-info":[{"award-number":["HHSN268201300001C"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Innovations in transgenic technology have facilitated improved xenograft survival. Additional gene expression appears to be necessary to overcome the remaining immune and biologic incompatibilities. We report for the first time the novel use of six\u2010gene modifications within a pig\u2010to\u2010baboon cardiac xenotransplantation model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Baboons (8\u201015\u00a0kg) underwent heterotopic cardiac transplantation using xenografts obtained from genetically engineered pigs. Along with previously described modifications (<jats:styled-content style=\"fixed-case\">GTKO<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> hCD<\/jats:styled-content>46), additional expression of human transgenes for thromboregulation (endothelial protein C receptor, tissue factor pathway inhibitor, thrombomodulin), complement inhibition (decay accelerating factor), and cellular immune suppression (<jats:styled-content style=\"fixed-case\">hCD<\/jats:styled-content>39, <jats:styled-content style=\"fixed-case\">hCD<\/jats:styled-content>47) was used. Immunosuppression consisted of targeted T\u2010cell and B\u2010cell depletion and conventional anti\u2010rejection agents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Heterotopic cardiac transplantations were performed without complication. Flow cytometry and immunohistochemistry on donor biopsies confirmed transgenic phenotype. In contrast to the prior three\u2010gene generation, significant coagulopathy or consumptive thrombocytopenia has not been observed in the six\u2010gene cohort. As a result, these recipients have experienced decreased bleeding\u2010related complications. Pro\u2010inflammatory responses also appear to be mitigated based on cytokine analysis. Baboons survived the critical 30\u2010day post\u2010operative period when mortality has historically been highest, with no evidence of graft rejection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The inclusion of additional human genes in genetically engineered pigs appears to confer superior xenograft outcomes. Introduction of these genes has not been associated with adverse outcomes. This multifactorial approach to genetic engineering furthers the prospect of long\u2010term cardiac xenograft survival and subsequent clinical application.<\/jats:p><\/jats:sec>","DOI":"10.1111\/xen.12330","type":"journal-article","created":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T09:46:43Z","timestamp":1506073603000},"source":"Crossref","is-referenced-by-count":27,"title":["Encouraging experience using multi\u2010transgenic xenografts in a pig\u2010to\u2010baboon cardiac xenotransplantation model"],"prefix":"10.1111","volume":"24","author":[{"given":"Joshua L.","family":"Chan","sequence":"first","affiliation":[{"name":"Cardiothoracic Surgery Research Program\/National Heart, Lung and Blood Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avneesh K.","family":"Singh","sequence":"additional","affiliation":[{"name":"Cardiothoracic Surgery Research Program\/National Heart, Lung and Blood Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip C.","family":"Corcoran","sequence":"additional","affiliation":[{"name":"Cardiothoracic Surgery Research Program\/National Heart, Lung and Blood Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin L.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Veterinary Resources National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billeta GT","family":"Lewis","sequence":"additional","affiliation":[{"name":"Division of Veterinary Resources National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Ayares","sequence":"additional","affiliation":[{"name":"Revivicor, Inc.  Blacksburg VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Vaught","sequence":"additional","affiliation":[{"name":"Revivicor, Inc.  Blacksburg VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Horvath","sequence":"additional","affiliation":[{"name":"Cardiothoracic Surgery Research Program\/National Heart, Lung and Blood Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4654-783X","authenticated-orcid":false,"given":"Muhammad M.","family":"Mohiuddin","sequence":"additional","affiliation":[{"name":"Cardiothoracic Surgery Research Program\/National Heart, Lung and Blood Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,9,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1171"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1711.2005.01398.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12219"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e318199c34f"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3089.2004.00155.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-3089.2000.00067.x"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.182865"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12133"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20080581"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mbc.0000240916.63521.2e"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12176"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1352.028"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e3182472850"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12209"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2005-869527"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOT.0b013e32835090f6"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12085"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2010.83"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12290"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12918"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3089.2012.00708.x"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2008.02210.x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12073"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3089.2009.00555.x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3089.2009.00537.x"}],"container-title":["Xenotransplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fxen.12330","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/xen.12330","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T04:44:06Z","timestamp":1694753046000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/xen.12330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,22]]},"references-count":25,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,11]]}},"alternative-id":["10.1111\/xen.12330"],"URL":"https:\/\/doi.org\/10.1111\/xen.12330","archive":["Portico"],"relation":{},"ISSN":["0908-665X","1399-3089"],"issn-type":[{"value":"0908-665X","type":"print"},{"value":"1399-3089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,22]]},"article-number":"e12330"}}