Lessons learned from first genetically-modified pig heart into human
patient

Date:
June 30, 2023
Source:
University of Maryland School of Medicine
Summary:
A new study has revealed the most extensive analysis to date on what
led to the eventual heart failure in the world's first successful
transplant of a genetically-modified pig heart into a human patient.


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FULL STORY ==========================================================================
A new study published today in The Lancet has revealed the most extensive analysis to date on what led to the eventual heart failure in the world's
first successful transplant of a genetically-modified pig heart into a
human patient.

This groundbreaking procedure was conducted by University of Maryland
School of Medicine (UMSOM) physician-scientists back in January 2022
and marked an important milestone for medical science.

The patient, 57-year-old David Bennett, Sr., was treated at the University
of Maryland Medical Center. He experienced strong cardiac function with
no obvious signs of acute rejection for nearly seven weeks after the
surgery. A sudden onset of heart failure led to his death two months
after the transplant. Since then, the transplant team has been conducting extensive studies into the physiologic processes that led to the heart
failure to identify factors that can be prevented in future transplants
to improve the odds of longer-term success.

"Our paper provides crucial insight into how a multitude of factors likely played a role in the functional decline of the transplanted heart,"
said study lead author Muhammad M. Mohiuddin, MD, Professor of Surgery
and Scientific/ Program Director of the Cardiac Xenotransplantation
Program at UMSOM. "Our goal is to continue moving this field forward as
we prepare for clinical trials of xenotransplants involving pig organs."
Mr. Bennett, who was in end-stage heart failure and nearing the end
of his life, did not qualify for a traditional heart transplant. The
procedure was authorized by the U.S. Food and Drug Administration under
its expanded access (compassionate use) provision.

"We were determined to shed light on what led to the heart transplant dysfunction in Mr. Bennett, who performed a heroic act by volunteering
to be the first in the world," said study co-author Bartley Griffith, MD, Professor of Surgery and The Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at UMSOM. "We want our next patient to not
only survive longer with a xenotransplant but to return to normal life
and thrive for months or even years." To better understand the processes
that led to dysfunction of the pig heart transplant, the research team performed extensive testing on the limited available tissues in the
patient. They carefully mapped out the sequence of events that led to
the heart failure demonstrating that the heart functioned well on imaging
tests like echocardiography until day 47 after surgery.

The new study confirms that no signs of acute rejection occurred during
the first several weeks after the transplant. Likely, several overlapping factors led to heart failure in Mr. Bennett, including his poor state
of health prior to the transplant that led him to become severely immunocompromised. This limited the use of an effective anti-rejection
regimen used in preclinical studies for xenotransplantation. As a
result, the researchers found, the patient was likely more vulnerable
to rejection of the organ from antibodies made by the immune system. The researchers found indirect evidence of antibody- mediated rejection based
on histology, immunohistochemical staining and single cell RNA analysis.

The use of an intravenous immunoglobulin, IVIG, a drug that contains antibodies, may also have contributed to damage to the heart muscle
cells. It was given to the patient twice during the second month after the transplant to help prevent infection, likely also triggering an anti-pig
immune response. The research team found evidence of immunoglobulin
antibodies targeting the pig vascular endothelium layer of the heart.

Lastly, the new study investigated the presence of a latent virus,
called porcine cytomegalovirus (PCMV), in the pig heart, which may have contributed to the dysfunction of the transplant. Activation of the
virus may have occurred after the patient's anti-viral treatment regimen
was reduced to address other health issues. This may have initiated an inflammatory response causing cell damage. However, there is no evidence
that the virus infected the patient or spread to organs beyond the
heart. Improved PCMV testing protocols have been developed for sensitive detection and exclusion of latent viruses for future xenotransplants.

Other UMSOM faculty co-authors of this study include: Avneesh K Singh,
PhD, Alison Grazioli, MD, Kapil Saharia, MD, Tianshu Zhang, MD, and
Christine Lau, MD.

"Valuable lessons can be learned from this groundbreaking surgery and
the courageous first patient, Mr. Bennett, that will better inform
us for future xenotransplants," said UMSOM Dean Mark T. Gladwin, MD,
Vice President for Medical Affairs, University of Maryland, Baltimore,
and the John Z. and Akiko K. Bowers Distinguished Professor. "In the
future, our team of surgeon- scientists will utilize newly designed
immune cell assays to monitor the patient more precisely in the days,
weeks, and months following the xenotransplant. This will provide
stricter control of the earliest signs of rejection and the promise
of a truly lifesaving innovation." Disclosures: Members of Program
in Cardiac Xenotransplantation at UMSOM received research funding from
United Therapeutics Corporation. Revivicor, Inc., provided the pigs, and Kiniksa Pharmaceuticals provided anti-CD40 antibodies. The University
of Maryland School of Medicine and the University of Maryland Medical
Center supported the remaining costs.

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========================================================================== Story Source: Materials provided by
University_of_Maryland_School_of_Medicine. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Muhammad M Mohiuddin, Avneesh K Singh, Linda Scobie, Corbin
E Goerlich,
Alison Grazioli, Kapil Saharia, Claire Crossan, Allen Burke,
Cinthia Drachenberg, Cihan Oguz, Tianshu Zhang, Billeta Lewis,
Alena Hershfeld, Faith Sentz, Ivan Tatarov, Sarah Mudd, Gheorghe
Braileanu, Kathryn Rice, John F Paolini, Kent Bondensgaard, Todd
Vaught, Kasinath Kuravi, Lori Sorrells, Amy Dandro, David Ayares,
Christine Lau, Bartley P Griffith.

Graft dysfunction in compassionate use of genetically engineered
pig-to- human cardiac xenotransplantation: a case report. The
Lancet, 2023; DOI: 10.1016/S0140-6736(23)00775-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/06/230630123122.htm

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