Ali Asghar, Kurome Mayuko, Kessler Barbara, Kemter Elisabeth, Wolf Eckhard
Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.
Center for Innovative Medical Models (CiMM), LMU Munich, Oberschleißheim, Germany.
Transpl Int. 2024 Dec 4;37:13681. doi: 10.3389/ti.2024.13681. eCollection 2024.
Xenotransplantation of porcine organs has made remarkable progress towards clinical application. A key factor has been the generation of genetically multi-modified source pigs for xenotransplants, protected against immune rejection and coagulation dysregulation. While efficient gene editing tools and multi-cistronic expression cassettes facilitate sophisticated and complex genetic modifications with multiple gene knockouts and protective transgenes, an increasing number of independently segregating genetic units complicates the breeding of the source pigs. Therefore, an optimal combination of essential genetic modifications may be preferable to extensive editing of the source pigs. Here, we discuss the prioritization of genetic modifications to achieve long-term survival and function of xenotransplants and summarise the genotypes that have been most successful for xenogeneic heart, kidney, and islet transplantation. Specific emphasis is given to the choice of the breed/genetic background of the source pigs. Moreover, multimodal deep phenotyping of porcine organs after xenotransplantation into human decedents will be discussed as a strategy for selecting essential genetic modifications of the source pigs. In addition to germ-line gene editing, some of these modifications may also be induced during organ preservation/perfusion, as demonstrated recently by the successful knockdown of swine leukocyte antigens in porcine lungs during perfusion.
猪器官的异种移植在临床应用方面已取得显著进展。一个关键因素是培育出用于异种移植的基因多重修饰的供体猪，以防止免疫排斥和凝血失调。虽然高效的基因编辑工具和多顺反子表达盒有助于通过多个基因敲除和保护性转基因实现复杂精细的基因修饰，但越来越多独立分离的遗传单位使供体猪的育种变得复杂。因此，关键基因修饰的最佳组合可能比供体猪的广泛编辑更可取。在此，我们讨论基因修饰的优先顺序，以实现异种移植的长期存活和功能，并总结在异种心脏、肾脏和胰岛移植中最成功的基因型。特别强调供体猪品种/遗传背景的选择。此外，将讨论把猪器官异种移植到人类死者体内后的多模态深度表型分析，作为选择供体猪关键基因修饰的一种策略。除了生殖系基因编辑外，其中一些修饰也可能在器官保存/灌注过程中诱导产生，最近在灌注过程中猪肺中成功敲低猪白细胞抗原就证明了这一点。
