Transplantation is the only long-term intervention available for patients with terminal heart failure. However, the number of donated human organs falls far short of the need, a situation that threatens the life of many potential recipients. Alternative techniques such as xenotransplantation are therefore urgently needed. The pig is the preferred donor species for a number or reasons, including size, anatomical and physiological similarities with humans, and efficient techniques for genetic engineering/gene editing.
Within the DFG Transregional Collaborative Research Center 127 “Biology of Xenogeneic Cell, Tissue and Organ Transplantation – from Bench to Bedside” the group of Eckhard Wolf generated – in collaboration with the US company Revivicor Inc. – genetically multi-modified pigs lacking αGal epitopes (GGTA1 knockout) and expressing human CD46 and human thrombomodulin. These modifications are required to overcome hyperacute and acute vascular rejection of pig-to-primate xenografts and to prevent coagulation dysregulation.
A paper published in Nature showed that hearts from these genetically multi-modified pigs can function in the long-term (for up to 195 days) after orthotopic transplantation (heart replacement) in baboons, the most stringent preclinical model for cardiac xenotransplantation. Bruno Reichart from the Walter Brendel Center of Experimental Medicine and his team performed a series of experiments finally resulting in consistent success of life-supporting cardiac xenotransplantation. Several improvements were key to the success, including specific perfusion preservation of the donor heart after explantation and during implantation as well as measures to prevent detrimental overgrowth of the xeno-heart in the recipient baboon.
Consistent long-term success in life-supporting orthotopic porcine heart transplantation in the most relevant preclinical model is regarded as a milestone on the way to clinical cardiac xenotransplantation.
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Consistent success in life-supporting porcine cardiac xenotransplantation.
Längin M, Mayr T, Reichart B, Michel S, Buchholz S, Guethoff S, Dashkevich A, Baehr A, Egerer S, Bauer A, Mihalj M, Panelli A, Issl L, Ying J, Fresch AK, Buttgereit I, Mokelke M, Radan J, Werner F, Lutzmann I, Steen S, Sjöberg T, Paskevicius A, Qiuming L, Sfriso R, Rieben R, Dahlhoff M, Kessler B, Kemter E, Klett K, Hinkel R, Kupatt C, Falkenau A, Reu S, Ellgass R, Herzog R, Binder U, Wich G, Skerra A, Ayares D, Kind A, Schönmann U, Kaup FJ, Hag Cl, Wolf E, Klymiuk N, Brenner P & Abicht JM
Nature. 2018 Dec 5. doi: 10.1038/s41586-018-0765-z.
Interview of Bruno Reichart by BR24 (in German only)