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Original ArticleBrief ReportFree Preview

Genetically Modified Porcine-to-Human Cardiac Xenotransplantation

List of authors.
  • Bartley P. Griffith, M.D.,
  • Corbin E. Goerlich, M.D., Ph.D.,
  • Avneesh K. Singh, Ph.D.,
  • Martine Rothblatt, Ph.D.,
  • Christine L. Lau, M.D.,
  • Aakash Shah, M.D.,
  • Marc Lorber, M.D.,
  • Alison Grazioli, M.D.,
  • Kapil K. Saharia, M.D.,
  • Susie N. Hong, M.D.,
  • Susan M. Joseph, M.D.,
  • David Ayares, Ph.D.,
  • and Muhammad M. Mohiuddin, M.D.

Summary

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis — findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.)

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Funding and Disclosures

Supported by the University of Maryland Medical Center and School of Medicine. The source animal was provided by Revivicor, and the KPL-404 antibody was provided by Kiniksa Pharmaceuticals, both in kind. CareDx and Karius analytics were provided in kind. No financial support was provided by Revivicor, United Therapeutics, Kiniksa Pharmaceuticals, or XVIVO. No federal funding was used for the experimental transplantation.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on June 22, 2022, at NEJM.org.

We thank the laboratory and clinical staff for their contribution to this case, referred to here as the University of Maryland Cardiac Xenotransplantation Working Group: members of the laboratory team not otherwise listed as authors (Tianshu Zhang, M.D., Ph.D., Ivan Tatarov, D.V.M., Alena Hershfeld, M.S., Gheorghe Braileanu, D.V.M., Ph.D., Faith Sentz, B.S., Billeta Lewis, M.S., and Sarah Mudd, B.S.R.N.), anesthesia staff (Patrick Odonkor, M.D., and Erik Strauss, M.D.), perfusion staff (Brian McCormick, C.C.P., Alyssa Druzgala, C.C.P., and Brian Donahue, C.C.P.), cardiology staff (Charles Hong, M.D., Ph.D., Albert Hicks, M.D., Manjula Ananthram, M.D., Gautam Ramani, M.D., Anuj Gupta, M.D., Mike Domanski, M.D., Timm Dickfield, M.D., Asadi Sadegh, M.D., and Peter Hanna, M.D.), nursing staff (Lauren Szostek, B.S.R.N., Sarah Cipriano, C.R.N.P., and Marco Oldsman, C.R.N.P.), ethics staff (Henry Silverman, M.D.), transplant pharmacy staff (Amanda Szczapanik, Pharm.D., and Myounghee Lee, Pharm.D.), surgical team (Jonathan Bromberg, M.D., Dan Maluf, M.D., Bradley Taylor, M.D., Chetan Pasrija, M.D., Shahab Toursavadkohi, M.D., Joseph Rabin, M.D., Barry Deatrick, M.D., Mehrdad Ghoreishi, M.D., and Laura DiChiacchio, M.D.), University of Maryland Transplant Pathology staff (Allen P. Burke, M.D., Kathryn Rice, M.D., and Ashley Celini, A.S.C.P.), staff of the National Institutes of Health Laboratory of Pathology (Stephen Hewitt, M.D., Ph.D., and Sabrina Ramelli, Ph.D.), staff of the University of Maryland School of Medicine Center for Innovative Biomedical Resources (including Veterinary Resources and the Flow Cytometry Facility), staff members at Kiniksa Pharmaceuticals (John F. Paolini, M.D., Ph.D., Randy Perrin, Ph.D., Manoj Samant, Ph.D., Moses Njenga, M.A., Mei Jiang, Ph.D., Becky Hamilton, B.Sc., Steve Schmitz, M.D., and Jennifer Ring, M.B.A.), staff members at CareDx (Robert Woodward, Ph.D., Alesha Luxon, B.S.N., C.C.T.C., and Alicia Griswold, B.S.R.N.), and staff members at Revivicor (Maria Kokkinaki, Ph.D., for porcine endogenous retrovirus polymerase-chain-reaction analysis, and Amy Dandro, M.Sc., for cytotoxicity assays); and the staff of Karius for thoughtful analyses.

Author Affiliations

From the Department of Surgery (B.P.G., C.E.G., A.K.S., C.L.L., A.S., M.M.M.), the Program in Trauma, R. Adams Cowley Shock Trauma Center, Department of Medicine (A.G.), the Institute of Human Virology, Division of Infectious Diseases (K.K.S.), and the Department of Medicine, Division of Cardiology (S.N.H., S.M.J.), University of Maryland School of Medicine, Baltimore, and United Therapeutics, Silver Spring (M.R., M.L.) — both in Maryland; and Revivicor, Blacksburg, VA (D.A.).

Dr. Griffith can be contacted at or at the Department of Surgery, University of Maryland School of Medicine, 110 S. Paca St., 7th Floor, Baltimore, MD 21201. Dr. Mohiuddin can be contacted at or at the Department of Surgery, University of Maryland School of Medicine, 10 S. Pine St., MSTF 434B, Baltimore, MD 21201.