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

利用转基因猪的组织和器官进行异种移植有可能解决人体移植材料严重短缺的问题。然而，在使用这种不协调的移植物之前，必须克服相当大的免疫障碍。α - 1-3半乳糖转移酶敲除的猪系已经克服了最初的超急性排斥反应障碍。现在需要进一步的改进，以提供足够的保护，防止急性体液异种移植排斥反应。人类补体调控基因在现有转基因动物中的表达不足，需要一种在器官中实现大量均匀表达的手段。最近的研究结果也强调了需要额外的转基因来减轻猪和人类抗凝血和抗炎系统之间的不相容性。我们建议用一种新颖的方法来解决这些问题。一条重新形成的人类人工染色体将被用作载体，将一组异种保护性转基因传递到猪体内。这项工作将与Xeno- Forschergruppe （FOR 535）密切合作进行。

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).