Project 1: Translating Renal Xenotransplantation

Massachusetts General Hospital, Boston MA

Investigators

Abstract

ABSTRACT Xenotransplantation using multiple gene edited (multi-GE) porcine organs is a promising approach to address organ shortage in organ transplantation. While we have achieved long-term renal xenograft survival exceeding one year in nonhuman primates (NHPs) using triple knockout (GalT, β4GalNT2 and CMAH KO - TKO) with seven human transgenes, thrombotic microangiopathy (TMA) and antibody-mediated rejection (AMR) remain the primary causes of the kidney xenograft loss. Since NHP natural antibody binding to GalT/β4GalNT KO - ‘double knock-out’ (DKO) cells is lower than to TKO cells, and similar to human antibody binding to TKO cells, we propose to transplant DKO kidneys with multi-GE as a more clinically relevant pretransplant model to evaluate incidence of TMA and AMR in the context of various clinically applicable immunosuppressive (IS) regimens. In addition, non-physiologic interactions between primate platelets and porcine von Willebrand factor (vWF), complement- mediated injury, and ischemia-reperfusion injury (IRI) have also each been implicated in TMA incidence and severity. Based on these considerations, we will investigate the following Aims in a well-established baboon model. Aim 1. To establish an optimized IS regimen for kidney xenotransplantation using a pig carbohydrate gene KO profile for NHP studies that is most relevant to predict human results; We will re-evaluate the requirement of costimulatory blockade (CoB) in baboon recipients of TKO vs. DKO Multi-GE porcine kidneys. Fc-modified-αCD154 mAb (TNX-1500) and non-activating αCD28 mAb (VEL-101), two clinically available costimulatory blockade (CoB) agents, will be compared to conventional IS for their potential to reduce the incidence of TMA/AMR. Aim 2. To evaluate humanized porcine vWF (h*pvWF) and C3- or C5-directed complement inhibition to prevent kidney xenograft TMA; We will evaluate whether h*pvWF in Multi-GE pigs, alone or with additional C3- or C5-directed complement inhibition, using a C3 or a C5 inhibitor, modulates TMA following kidney xenotransplantation. Aim 3. To minimize ischemia reperfusion injury (IRI) by normothermic machine perfusion (NMP), alone or with additional CD11b blockade. We hypothesize that minimizing IRI by NMP and blocking CD11b, will attenuate innate immune activation and ameliorate TMA, improving kidney xenotransplant outcomes.