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2016-06-29Zeitschriftenartikel DOI: 10.1038/srep29081
Efficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing
dc.contributor.authorFischer, Konrad
dc.contributor.authorKraner-Scheiber, Simone
dc.contributor.authorPetersen, Björn
dc.contributor.authorRieblinger, Beate
dc.contributor.authorBuermann, Anna
dc.contributor.authorFlisikowska, Tatiana
dc.contributor.authorFlisikowski, Krzysztof
dc.contributor.authorChristan, Susanne
dc.contributor.authorEdlinger, Marlene
dc.contributor.authorBaars, Wiebke
dc.contributor.authorKurome, Mayuko
dc.contributor.authorZakhartchenko, Valeri
dc.contributor.authorKessler, Barbara
dc.contributor.authorPlotzki, Elena
dc.contributor.authorSzczerbal, Izabela
dc.contributor.authorSwitonski, Marek
dc.contributor.authorDenner, Joachim
dc.contributor.authorWolf, Eckhard
dc.contributor.authorSchwinzer, Reinhard
dc.contributor.authorNiemann, Heiner
dc.contributor.authorKind, Alexander
dc.contributor.authorSchnieke, Angelika
dc.date.accessioned2018-05-07T19:08:18Z
dc.date.available2018-05-07T19:08:18Z
dc.date.created2016-07-26
dc.date.issued2016-06-29none
dc.identifier.otherhttp://edoc.rki.de/oa/articles/re4aoMhUIsxE/PDF/23KiJ6dPp2p0s.pdf
dc.identifier.urihttp://edoc.rki.de/176904/2353
dc.description.abstractXenotransplantation from pigs could alleviate the shortage of human tissues and organs for transplantation. Means have been identified to overcome hyperacute rejection and acute vascular rejection mechanisms mounted by the recipient. The challenge is to combine multiple genetic modifications to enable normal animal breeding and meet the demand for transplants. We used two methods to colocate xenoprotective transgenes at one locus, sequential targeted transgene placement - ‘gene stacking’, and cointegration of multiple engineered large vectors - ‘combineering’, to generate pigs carrying modifications considered necessary to inhibit short to mid-term xenograft rejection. Pigs were generated by serial nuclear transfer and analysed at intermediate stages. Human complement inhibitors CD46, CD55 and CD59 were abundantly expressed in all tissues examined, human HO1 and human A20 were widely expressed. ZFN or CRISPR/Cas9 mediated homozygous GGTA1 and CMAH knockout abolished α-Gal and Neu5Gc epitopes. Cells from multi-transgenic piglets showed complete protection against human complement-mediated lysis, even before GGTA1 knockout. Blockade of endothelial activation reduced TNFα-induced E-selectin expression, IFNγ-induced MHC class-II upregulation and TNFα/cycloheximide caspase induction. Microbial analysis found no PERV-C, PCMV or 13 other infectious agents. These animals are a major advance towards clinical porcine xenotransplantation and demonstrate that livestock engineering has come of age.eng
dc.language.isoeng
dc.publisherRobert Koch-Institut, Infektionskrankheiten / Erreger
dc.subject.ddc610 Medizin
dc.titleEfficient production of multi-modified pigs for xenotransplantation by ‘combineering’, gene stacking and gene editing
dc.typeperiodicalPart
dc.identifier.urnurn:nbn:de:0257-10045810
dc.identifier.doi10.1038/srep29081
dc.identifier.doihttp://dx.doi.org/10.25646/2278
local.edoc.container-titleScientific Reports
local.edoc.fp-subtypeArtikel
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttp://www.nature.com/articles/srep29081
local.edoc.container-publisher-nameNature Publishing Group
local.edoc.container-volume6
local.edoc.container-issue29081
local.edoc.container-year2016

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