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Pig-to-human heart xenotransplantation in two recently deceased human recipients

Nature Medicine volume 29, pages 1989–1997 (2023)Cite this article

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Abstract

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

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Fig. 1: Study timelines and cardiac and systemic hemodynamic measurements.
Fig. 2: Xenograft histology and immunohistochemistry.
Fig. 3: Infectious diseases surveillance in donor pigs and xenograft heart recipients.
Fig. 4: Anti-pig IgM and IgG detection by flow cytometry and complement-dependent cytotoxicity assays.
Fig. 5: Cytokine responses and inflammatory markers in xenograft heart recipients.

Data availability

The data that support the findings of this study, including de-identified decedent data, are available on request from the corresponding authors, N.M. and R.A.M. The data are not publicly available due to containing information that could compromise the privacy of research subjects. Data related to the genetics of the 10GE donor pigs are the proprietary information of United Therapeutics Corporation, PBC, and therefore are restricted. Source data are provided with this paper.

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Acknowledgements

The authors sincerely thank the families of the decedents for their generous donation to science. The authors also thank M. Rothblatt, CEO of United Therapeutics Corporation, PBC, and United Therapeutics Corporation, PBC, for funding support. For significant contributions to the performance of this study the authors thank I. Ifraimova, H. Datta, K. Cantor, E. Finegan, F. Matteo, M. VanName, K. Abinnante, R. Vania-Velasco, L. Herbold, N. Portello, R. Venick, S. Mompoint, P. Donohue, K. Allen, G. Boulton, J. Pavone, A. Eutsay, B. Sullivan, S. Castiglioni, A. Eremiev, M. E. Gumina, N. Ostberg, N. Uzoigwe, C. Deterville, P. Hotchkis, R. Rothstein, C. Hickson, S. Bennett, P. Alcide, M. Reeb, K. Silik, T. Hsiung, T. Beaulieu, F. Hill, N. Albright, A. Merrifield, M. Peng, M. McBridge, J. Ciolko, E. Duggan, D. Wolbrom, J. Beagle, A. Dandro, T. K. Adams, L. Sorrells, R. Herati, K. Tokoro and T. Katsarou (both supported by NCI NIH EDRN U01 CA214195), the Boeke Laboratory Team, NYU Langone Health Nursing Leadership, NYU Transplant Research Team, and the NYU Langone Health Center for Biospecimen Research and Development (CBRD), Histology and Immunohistochemistry Laboratory (RRID:SCR_018304), supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant (NIH/NCI P30CA016087). The authors also appreciate B. Parent, JD, Director of Transplant Ethics and Policy Research at NYU Grossman School of Medicine, for his contributions.

Author information

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, New York University Langone Health, New York, NY, USA

    Nader Moazami, Les James, Syed T. Hussain, Justin Chan, Harvey Pass, Chandra Goparaju & Deane E. Smith

  2. New York University Langone Transplant Institute, New York, NY, USA

    Jeffrey M. Stern, Karen Khalil, Jacqueline I. Kim, Massimo Mangiola, Elaina P. Weldon, Nikki Lawson, Nicole M. Ali, Vasishta S. Tatapudi, Adam Griesemer, Sapna A. Mehta & Robert A. Montgomery

  3. Department of Pathology, New York University Langone Health, New York, NY, USA

    Navneet Narula

  4. Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA

    Larisa Kagermazova & Jef D. Boeke

  5. Department of Surgery, New York University Langone Health, New York, NY, USA

    Greta L. Piper & Dorry L. Segev

  6. Department of Anesthesiology, New York University Langone Health, New York, NY, USA

    Philip M. Sommer, Jennie Ngai & Thomas Jan

  7. Division of Cardiology, New York University Langone Health, New York, NY, USA

    Alex Reyentovich, Daniel Bamira, Tajinderpal Saraon, Bernard S. Kadosh, Michael DiVita & Randal I. Goldberg

  8. Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA

    Dorry L. Segev

  9. New York University Grossman School of Medicine, New York University, New York, NY, USA

    Shivani Bisen, Ian S. Jaffe & Haley Kowalski

  10. Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

    Benjamin Piegari

  11. Revivicor, Inc., Blacksburg, VA, USA

    Maria Kokkinaki, Jeffrey Monahan, Lori Sorrells, Lars Burdorf & David Ayares

  12. Institute for Systems Genetics, New York University Grossman School of Medicine, New York, NY, USA

    Jef D. Boeke

  13. Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA

    Brendan Keating

  14. United Therapeutics Corporation, Silver Spring, MD, USA

    Marc Lorber

Authors
  1. Nader Moazami
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  2. Jeffrey M. Stern
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  3. Karen Khalil
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Contributions

Concept or study design: N.M., J.M.S., K.K., J.I.K., M.M., E.P.W., N.L., G.L.P., P.M.S., A.R., J.N., V.S.T., D.L.S., L.B., J.D.B., H.P., B.K., D.A., M.L., A.G., S.A.M., D.E.S., R.A.M. Acquisition of data: N.M., J.M.S., K.K., J.I.K., N.N., M.M., E.P.W., L.K., L.J., N.L., G.L.P., P.M.S., A.R., D.B., T.S., B.S.K., M.D., R.I.G., S.T.H., J.C., J.N., T.J., N.M.A., V.S.T., S.B., I.S.J., B.P., H.K., M.K., J.M., L.S., L.B., J.D.B., H.P., C.G., B.K., D.A., A.G., D.E.S., R.A.M. Analysis: J.M.S., K.K., J.I.K., N.N., M.M., L.K., D.B., M.K., J.M., L.S., J.D.B., H.P., C.G., B.K., A.G., R.A.M. Interpretation of data: N.M., J.M.S., K.K., J.I.K., N.N., M.M., L.K., A.R., D.B., T.S., B.S.K., M.D., R.I.G., N.M.A., V.S.T., D.L.S., M.K., J.M., L.S., J.D.B., H.P., C.G., B.K., D.A., M.L., A.G., S.A.M., D.E.S., R.A.M. Drafting the work or revising it critically for important intellectual content: N.M., J.M.S., K.K., J.I.K., N.N., M.M., E.P.W., A.R., D.B., D.L.S., J.D.B., H.P., B.K., D.A., M.L., A.G., S.A.M., D.E.S., R.A.M.

Corresponding authors

Correspondence to Nader Moazami or Robert A. Montgomery.

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Competing interests

The authors declare that research support and funding was provided by Lung Biotechnology, a wholly owned subsidiary of the United Therapeutics Corporation, PBC. M.K., J.M., L.S., L.B., D.A. are employed by Revivicor, Inc. M.L. is employed by United Therapeutics Corporation, PBC. R.A.M. is on scientific advisory boards for eGenesis, Sanofi, Regeneron, CareDx and Hansa Biopharma, is a consultant to Recombinetics, reports consulting fees from Hansa Medical, Regeneron, ThermoFisher Scientific, Genentech, CareDx, One Lambda, ITB Med, Sanofi and PPD Development, and reports grant support from Hansa Biopharma, all unrelated to the present work. R.A.M. also reports grant support from United Therapeutics Corporation, PBC. D.L.S. is a consultant to AstraZeneca, Novavax, Novartis, CareDx, Transmedics, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt and ThermoFisher Scientific, reports honoraria from Sanofi, AstraZeneca, Optum, CareDx and Novartis, and grant support from the National Institutes of Health, all unrelated to the present work. J.D.B. is a founder and director of CDI Labs, Inc., a founder of and consultant to Neochromosome, Inc., a founder, SAB member of and consultant to ReOpen Diagnostics, LLC, and serves or served on the Scientific Advisory Board of the following: Logomix, Inc., Modern Meadow, Inc., Rome Therapeutics, Inc., Sample6, Inc., Sangamo, Inc., Tessera Therapeutics, Inc. and the Wyss Institute, all unrelated to the present work. K.K. is a consultant to ProMedCARE Solutions, Inc., unrelated to the present work. All other authors have no competing interests.

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Nature Medicine thanks Hidetaka Hara, Joren Madsen and Muhammad Mohiuddin for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Additional laboratory assessments of xenograft hearts.

Clinical lab testing of serial blood samples collected from each recipient throughout the duration of the study: a, white blood cells; b, platelets; c, hemoglobin; d, international normalized ratio (INR); e, high-sensitivity troponin I; f, B-type natriuretic peptide (BNP); g, aspartate aminotransferase (AST), alanine aminotransferase (ALT); h, alkaline phosphatase (ALP), total bilirubin (Tb).

Extended Data Fig. 2 Transesophageal echocardiograms (TEE) of xenograft hearts 1 and 2.

a, TEE depicting xenograft heart 1 at the time of transplant. b, TEE depicting xenograft heart 2 at the time of transplant. Images depict a four-chamber view of the heart obtained from a deep transgastric (xenograft heart 1) and mid-esophageal (xenograft heart 2) TEE window. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Extended Data Fig. 3 12-lead electrocardiograms (EKG) of xenograft hearts 1 and 2.

a, 12-lead EKG performed on POD 2 on xenograft heart 1. Image shows a junctional rhythm without p waves, QRS duration of 116 milliseconds (ms), QT interval of 482 ms, and QTc interval of 555 ms. b, 12-lead EKG performed on POD 2 on xenograft heart 2. Image shows normal sinus rhythm with PR interval of 128 ms, QRS duration of 74 ms, QT interval of 364 ms, and QTc interval of 492 ms.

Extended Data Fig. 4 qRT-PCR and qPCR analysis of porcine organs.

RNA and DNA were extracted from the indicated organs from donor animals corresponding to recipient 1 (top) and 2 (bottom) and the qRT-PCR was performed on RNA (a, c) and qPCR was performed on DNA (b, d).

Extended Data Fig. 5 Analysis for peripheral blood porcine macrochimerism.

Peripheral blood was examined for the presence of pig macrochimerism at 4 time points for each recipient. Samples were stained with antibodies that bind to pig CD45 and human MHC 1 and analyzed using flow cytometry. a, Analysis of pig cells in a control pig sample. b, Analysis of sample from xenograft heart recipient 2 at 24 hours after xenotransplantation. c, Flow cytometry gating strategy.

Extended Data Table 1 Echocardiographic measurements of xenograft hearts
Full size table
Extended Data Table 2 Electrophysiological measurements
Full size table
Extended Data Table 3 Baseline zoonosis
Full size table

Supplementary information

Supplementary Information

Supplementary Fig. 1, Supplementary Tables 1–3, Supplementary Video Fig. Legends 1 and 2

Reporting Summary

Supplementary Video 1

TEE videos of xenograft heart 1. Serial TEEs of the first decedent from sequential postoperative days (PODs). Imaging shows a four-chamber view of the heart obtained from a deep transgastric TEE window. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Supplementary Video 2

TEE videos of xenograft heart 2. Serial TEEs of the second decedent from sequential postoperative days (PODs). Imaging shows a four-chamber view of the heart obtained from a mid-esophageal TEE window. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Source data

Source Data Fig. 3

Unprocessed gels for Fig. 3a (recipient 1 PERV) and 3b (recipient 2 PERV)

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Moazami, N., Stern, J.M., Khalil, K. et al. Pig-to-human heart xenotransplantation in two recently deceased human recipients. Nat Med 29, 1989–1997 (2023). https://doi.org/10.1038/s41591-023-02471-9

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