New England Surgical Society

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Prolonged Survival of Genetically Modified Pig Livers During Machine Perfusion With Human Blood
*Taylor M Coe1, *Danielle Detelich1, *Charles G Rickert1, *Cailah Carroll1, *Nikolaos Serifis1, *Rudy Matheson1, *Siavash Raigani1, *Ivy Rosales1, *Wenning Qin2, *Yinan Kan2, *Jacob Layer2, *Michele Youd2, *William Westlin2, *Shoko Kimura1, *Agnes Azimzadeh1, *Luhan Yang2, James F Markmann1
1Massachusetts General Hospital, Boston, MA;2eGenesis, Cambridge, MA

Objective: Study the human response to genetically modified pig livers utilizing ex-vivo liver perfusion with human blood.Design: Livers from wild type (WT) (n=2), GTKO.CD55 (n=4) and three variations of multiplex genome engineered pigs (Pig 2.0; n=7) that contained triple knockout for αGal, β4Gal, CMAH plus genetic modifications targeting complement, immune and inflammation regulation, underwent normothermic machine perfusion using human whole blood. Perfusion was continued until graft failure, defined by decreased blood flow due to elevated vascular resistance. Standard laboratory analyses & tissue histopathology were performed.Results:Livers in all groups demonstrated increased vascular resistance. However, this was evident earlier and progressed faster in the WT and GTKO.CD55 groups compared to the Pig 2.0 group. The red blood cell count remained more stable over time in the Pig 2.0 livers while the platelet count decreased in all livers. The lactate decreased and remained lower in the 2.05 and 2.09 livers when compared to the WT and GTKO.CD55 livers. Histologically, Pig 2.0 livers exhibited preserved hepatic architecture with mild inflammation and sinusoidal IgG and IgM staining confirmed antibody deposition, but C4d was negative. In contrast, WT livers sustained focal ischemic necrosis with a greater intensity of IgG and IgM staining and C4d positivity. Conclusions: In this ex vivo perfusion model, Pig 2.0 livers achieved prolonged function, improved lactate clearance, a more stable red blood cell count and diminished antibody and complement deposition compared to WT or GTKO.hCD55 livers. The profound platelet loss was not attenuated with current modifications that do not address coagulation dysregulation.



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