Investigational New Drug Enabling Nonclinical Study of Xenogeneic Life‐Supporting Porcine Kidneys With 10 Gene Edits (10 GE) in a Nonhuman Primate Test System

This Investigational New Drug (IND) enabling study evaluated life-supporting kidney xenotransplantation using porcine source animals with 10 gene edits (10 GE) in a nonhuman primate (NHP) test system. Twelve baboons received xenografts with either calcineurin inhibitor (CNI)-based or CD40/154 costimulation blockade immunosuppression. Source-specific screening prevented early xenograft antibody-mediated rejection in recipients, and clinically relevant preservation with hypothermic machine perfusion-maintained xenograft viability after off-site procurement at a high health herd facility. No zoonotic infections were detected. Six of 12 recipients achieved survival >3 months without evidence of cell- or antibody-mediated rejection. CNI-based regimens were well-tolerated and achieved the longest survivals to date using this approach, contingent on maintenance of therapeutic drug levels. However, xenograft loss among recipients of each immunosuppression regimen was associated with complement activation and microangiopathy, despite 10 GE Xenokidney expression of hCD46 and hCD55. Complement activation, potentially worsened by infection-related inflammation, may lead to long-term 10 GE Xenokidney failure.