Pig‐to‐baboon lung xenotransplantation: Extended survival with targeted genetic modifications and pharmacologic treatments

摘要

Galactosyl transferase knock‐out pig lungs fail rapidly in baboons. Based on previously identified lung xenograft injury mechanisms, additional expression of human complement and coagulation pathway regulatory proteins, anti‐inflammatory enzymes and self‐recognition receptors, and knock‐down of the β4Gal xenoantigen were tested in various combinations. Transient life‐supporting GalTKO.hCD46 lung function was consistently observed in association with either hEPCR (n?=?15), hTBM (n?=?4), or hEPCR.hTFPI (n?=?11), but the loss of vascular barrier function in the xenograft and systemic inflammation in the recipient typically occurred within 24?h. Co‐expression of hEPCR and hTBM (n?=?11) and additionally blocking multiple pro‐inflammatory innate and adaptive immune mechanisms was more consistently associated with survival >1?day, with one recipient surviving for 31?days. Combining targeted genetic modifications to the lung xenograft with selective innate and adaptive immune suppression enables prolonged initial life‐supporting lung function and extends lung xenograft recipient survival, and illustrates residual barriers and candidate treatment strategies that may enable the clinical application of other organ xenografts.