*Purpose: Organ shortage remains a major limitation within transplantation, with waiting lists greatly outpacing the number of donors available. Pig organs offer significant advantages for transplant into humans including having similar sized organs which are mature at ~6 months of age. Furthermore, there have been significant recent advances in ethical research using recently deceased brain-dead human donors, and genetic knockouts of potent xeno-antigens such as the alpha1,3-galactosyltransferase (α-1,3-Gal) gene. In September and November 2021, pig kidney and thymus xenografts, with the α-1,3-Gal transferase gene knocked out, were transplanted to the femoral vessels of two decedents. The primary aims were to assess: (a) hyper-acute antibody mediated rejection (AbMR); (b) sustained urine production and (c) clinically meaningful reduction in creatinine.

*Methods: Secondary analyses include whole genome-sequencing (WGS) and additional omic studies across longitudinally collected samples over the xenotransplant procedure, to impute and prioritize xeno-antigens for deeper functional interrogation. DNA and protocol tissue biopsies, blood and urine were sampled across the predefined timepoints during the ~52-54 hour procedures.

*Results: WGS, performed at ~100x fold coverage of mean depth reads across the human decedents and pig donor genomes, were processed according to best practices pipelines, aligned using comparative genomics, and subjected to a number of donor-recipient (D-R) loss-of-function (LoF) and custom allo- and xeno-genic machine learning pipelines. Whole-proteome, metabolome and transcriptome profiling was performed across 12-15 timepoints, and the resulting multiomic datasets were subjected to integrative personal omic profiling (iPOP).

*Conclusions: These pipelines generated over 100 non-HLA/non-swine leukocyte antigens (SLA) xenogenic targets which were prioritized as candidates along with HLA and SLA targets for xeno-antibody screening in the decedents sera across the study timepoints.

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