First clinical-grade transplant of gene-edited pig kidneys into brain-
dead human

Date:
January 20, 2022
Source:
University of Alabama at Birmingham
Summary:
Researchers have announced the first peer-reviewed research
outlining the successful transplant of genetically modified,
clinical-grade pig kidneys into a brain-dead human individual,
replacing the recipient's native kidneys. These positive results
demonstrate how xenotransplantation could address the worldwide
organ shortage crisis.



FULL STORY ==========================================================================
The University of Alabama at Birmingham Marnix E. Heersink School of
Medicine announces today the first peer-reviewed research outlining the successful transplant of genetically modified, clinical-grade pig kidneys
into a brain- dead human individual, replacing the recipient's native
kidneys. These positive results demonstrate how xenotransplantation
could address the worldwide organ shortage crisis.


==========================================================================
In the study published in the American Journal of Transplantation, UAB researchers tested the first human preclinical model for transplanting genetically modified pig kidneys into humans. The study recipient had two genetically modified pig kidneys transplanted in his abdomen after his
native kidneys were removed. The organs were procured from a genetically modified pig at a pathogen-free facility.

"Along with our partners, we have made significant investments in xenotransplantation for almost a decade hoping for the kinds of results published today," said Selwyn Vickers, M.D., dean of the UAB Heersink
School of Medicine and CEO of the UAB Health System and UAB/Ascension
St. Vincent's Alliance. "Today's results are a remarkable achievement
for humanity and advance xenotransplant into the clinical realm. With
this study, our research teams have also demonstrated that the decedent
model has significant potential to propel the xenotransplantation field forward." For the first time, the pig kidneys transplanted were taken
from pigs that had been genetically modified with 10 key gene edits
that may make the kidneys suitable for transplant into humans. This
process demonstrates the long-term viability of the procedure and how
such a transplant might work in the real world. The transplanted kidneys filtered blood, produced urine and, importantly, were not immediately
rejected. The kidneys remained viable until the study was ended, 77
hours after transplant.

"This game-changing moment in the history of medicine represents a
paradigm shift and a major milestone in the field of xenotransplantation,
which is arguably the best solution to the organ shortage crisis," said
Jayme Locke, M.D., director of the Comprehensive Transplant Institute
in UAB's Department of Surgery and lead surgeon for the study. "We have
bridged critical knowledge gaps and obtained the safety and feasibility
data necessary to begin a clinical trial in living humans with end-stage
kidney failure disease." Gene editing in pigs to reduce immune rejection
has made organ transplants from pigs to humans possible, which could
offer help to thousands of people who face organ failure, disease or
injury. The natural lifespan of a pig is 30 years, they are easily bred
and can have organs of similar size to humans.



========================================================================== Genetically modified pig kidneys have been extensively tested in non-human primates. In addition to testing in non-human primates, evaluating
genetically modified pig kidneys in a human preclinical model research
may provide important information about the potential safety and efficacy
of kidneys in human transplant recipients, including in clinical trials.

"This human preclinical model is a way to evaluate the safety and
feasibility of the pig-to-non-human primate model, without risk to a
living human," Locke added. "Our study demonstrates that major barriers
to human xenotransplantation have been surmounted, identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans,
and lays the foundation for the establishment of a novel preclinical human model for further study." This effort is supported by biotechnology
pioneer United Therapeutics Corporation, which awarded a grant to UAB
to launch the innovative xenotransplantation program. Revivicor, Inc.,
a subsidiary of United Therapeutics, provided the genetically modified
pig that was the source of the investigational xenotransplant kidneys
called UKidney[TM].

"All of us at Revivicor are in awe of the historic achievements at UAB
with our investigational 10-gene xenokidney, or UKidney," said David
Ayares, Ph.D., Chief Scientific Officer of Revivicor and a trailblazing
genetic engineer since his early work cloning the world's first pigs
and the first alpha-Gal knockout pigs. "We feel confident that this
UKidney may turn out to be a life-saving solution for thousands of people
on dialysis, subject to successful completion of our clinical trials
and achievement of FDA approval in the next several years." About the
study The peer-reviewed research is a study of ambitious scope and great significance, given that more than 800,000 Americans are living with
kidney failure. Most never make it to the waiting list, and far too few
human organs are available to put a dent in that number. Although dialysis
can sustain life for some time, transplantation offers a better quality
of life and a longer life for the few individuals who can gain access
to transplantation. Each stage of this decedent xenotransplant study approximated the steps that might be taken in a Phase I xenotransplant
clinical trial:
* The kidneys were removed from a donor pig housed at a pathogen-free,
surgically clean facility. The kidneys were then stored, transported
and processed for implantation, just as human kidneys are.

* Before surgery, the brain-dead recipient and donor animal
underwent a
crossmatch compatibility test to determine whether the genetically
modified pig kidney and its intended recipient were a good tissue
match.

A crossmatch is done for every human-to-human kidney transplant;
however, this pig-to-human tissue-match test was developed at
UAB and marked the first time a prospective crossmatch has been
validated between the two species.

* The pig kidneys were placed in the exact anatomic locations used for
human donor kidneys, with the same attachments to the renal artery,
renal vein and the ureter that carries urine from the kidney to
the bladder.

* The brain-dead recipient received standard immune-suppression
therapy
used in human-to-human kidney allotransplantation.



==========================================================================
The study was conducted to meet the standards directly comparable to
those that would apply to a Phase I human clinical trial, mirroring every
step of a standard transplant between humans. It included Institutional
Review Board and Institutional Animal Care and Use Committee approval,
a tissue compatibility confirmation before starting the operations,
using the standard procedures of human-to-human transplants to remove, preserve, transport and transplant the kidneys into a human, and giving
the standard immunosuppression therapy to the recipient.

The critical need for other organ donation options Kidney disease kills
more people each year than breast or prostate cancer, according to the
National Institute of Diabetes and Digestive and Kidney Diseases. Although transplantation is the gold standard treatment for end-stage kidney
disease, fewer than 25,000 kidney transplants are performed each year in
the United States and 240 Americans on dialysis die every day. Many of
these deaths could be prevented if an unlimited supply of kidneys were available for transplant.

The wait for a deceased donor kidney can be as long as five years, and
in many states, it is closer to 10 years. Almost 5,000 people per year
die waiting on a kidney transplant.

========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Tyler
Greer. Note: Content may be edited for style and length.


========================================================================== Related Multimedia:
* YouTube_video:_Pig-to-human_kidney_transplant_3D_animation ========================================================================== Journal Reference:
1. Paige M. Porrett, Babak J. Orandi, Vineeta Kumar, Julie Houp,
Douglas
Anderson, A. Cozette Killian, Vera Hauptfeld‐Dolejsek,
Dominque E.

Martin, Sara Macedon, Natalie Budd, Katherine L. Stegner, Amy
Dandro, Maria Kokkinaki, Kasinath V. Kuravi, Rhiannon D. Reed,
Huma Fatima, John T. Killian, Gavin Baker, Jackson Perry, Emma
D. Wright, Matthew D.

Cheung, Elise N. Erman, Karl Kraebber, Tracy Gamblin, Linda Guy,
James F.

George, David Ayares, Jayme E. Locke. First clinical‐grade
porcine kidney xenotransplant using a human decedent model. American
Journal of Transplantation, 2022; DOI: 10.1111/ajt.16930 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220120091128.htm

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