Mammalian artificial chromosomes for gene transfer in livestock: Production of multi-transgenic pigs for xenotransplantation

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Xenotransplantation using tissues and organs from genetically modified pigs has the potential to fulfil the serious shortage of material available for human transplantation. However, considerable immunological barriers must be overcome before such discordant grafts can be used. The generation of α1-3 galactosyltransferase knock out pig lines has surmounted the initial obstacle of hyperacute rejection. Further improvements are now necessary to provide adequate protection against acute humoral xenograft rejection. The expression of human complement regulator transgenes in existing transgenic animals is inadequate, and a means of achieving abundant uniform expression in the organ is required. Recent findings have also highlighted the need for additional transgenes to alleviate incompatibilities between the porcine and human anticoagulation and antiinflammatory systems. We propose to address these problems using a novel approach. A de novo formed human artificial chromosome will be used as a vector to deliver sets of xenoprotective transgenes into pigs. The work will be carried out in close collaboration with the Xeno- Forschergruppe (FOR 535).