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Genetic Engineering of Donor Pig for the First Human Cardiac Xenotransplantation: Combatting Rejection, Coagulopathy, Inflammation, and Excessive Growth

  • Heart Failure (HJ Eisen, Section Editor)
  • Published:
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Abstract

Purpose of Review

The first successful pig to human cardiac xenotransplantation in January 2022 represented a major step forward in the fields of heart failure, immunology, and applied genetic engineering, using a 10-gene edited (GE) pig. This review summarizes the evolution of preclinical modelling data which informed the use of each of the 10 genes modified in the 10-GE pig: GGTA1, Β4GalNT2, CMAH, CD46, CD55, TBM, EPCR, CD47, HO-1, and growth hormone receptor.

Recent Findings

The translation of the 10-GE pig from preclinical modelling to clinical compassionate xenotransplant use was the culmination of decades of research combating rejection, coagulopathy, inflammation, and excessive xenograft growth.

Summary

Understanding these 10 genes with a view to their combinatorial effects will be useful in anticipated xenotransplant clinical trials.

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Abbreviations

EPCR:

Endothelial protein C receptor

Gal:

Galactose-alpha-1,3-galactose

GE:

Genetically engineered

GHR:

Growth hormone receptor

GHRKO:

Growth hormone receptor knockout

HAR:

Hyperacute rejection

HO-1:

Heme oxygenase-1

KO:

Knockout

Neu5Gc:

N-glycolylneuraminic acid

NHP:

Non-human primate

SDa:

SD antigen

TBM:

Thrombomodulin

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Author information

Authors and Affiliations

  1. Department of Surgery, University of Maryland, Baltimore, MD, USA

    Shreya Singireddy

  2. Program in Cardiac Xenotransplantation, Department of Surgery, University of Maryland, Baltimore, MD, USA

    Andy Tully, Javier Galindo, Avneesh K. Singh & Muhammad M. Mohiuddin

  3. Revivicor Inc, Blacksburg, VA, USA

    David Ayares

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  1. Shreya Singireddy
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Corresponding author

Correspondence to Muhammad M. Mohiuddin.

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Conflict of Interest

Dr. Ayares is the President and CEO of Revivicor and reports other from Revivicor Inc. and personal fees from Revivicor Inc. In addition, Dr. Ayares has a patent on Multitransgenic pigs for xenotransplantation issued. Dr. Mohiuddin reports research funding and pigs provided by United Therapeutics, Inc. and drugs provided by Eledon Pharmaceuticals, Tonix Pharmaceuticals, and Kiniksa Pharmaceuticals. In addition, Dr. Mohiuddin has a patent pending with Kiniksa Pharmaceuticals on the Use of drug KPL 404 to overcome rejection. The other authors have no disclosures to report.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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Singireddy, S., Tully, A., Galindo, J. et al. Genetic Engineering of Donor Pig for the First Human Cardiac Xenotransplantation: Combatting Rejection, Coagulopathy, Inflammation, and Excessive Growth. Curr Cardiol Rep 25, 1649–1656 (2023). https://doi.org/10.1007/s11886-023-01978-4

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