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.
"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."
UAB announces first clinical-grade transplant of gene-edited pig kidneys
into brain-dead human
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.
Transplant recipient Jim Parsons helps open doors to the future of organ
transplantation
This scientific and medical breakthrough would not have been possible
without Jim Parsons, the recipient, or his family.
Parsons, 57, was a registered organ donor through Legacy of Hope, Alabama's
organ procurement organization, and he had longed to have his organs help
others upon his death; but his organs were not suitable for donation. His
family permitted UAB to maintain Parsons on a ventilator to keep his body
functioning during the study. His native kidneys were removed, and two
genetically modified pig kidneys were transplanted.
"Mr. Parsons and his family allowed us to replicate precisely how we would
perform this transplant in a living human. Their powerful contribution will
save thousands of lives, and that could begin in the very near future,"
Locke said. "Mr. Parsons' gift honors his legacy and firmly establishes the
viability, safety and feasibility of this preclinical model. Because of his
gift, we have proposed this to be known as 'The Parsons Model.'"
Parsons' ex-wife, Julie O'Hara, and their children, Ally, David and Cole,
made the decision (along with Jim's sisters and mother) to take part in the
study after they were approached by Alan Spriggs with Legacy of Hope and
Locke.
"Jim was a never-met-a-stranger kind of guy who would talk to anyone and had
no enemies—none," O'Hara said. "Jim would have wanted to save as many people
as he could with his death, and if he knew he could potentially save
thousands and thousands of people by doing this, he would have had no
hesitation. Our dream is that no other person dies waiting for a kidney, and
we know that Jim is very proud that his death could potentially bring so
much hope to others."
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.
Reference:
First clinical-grade porcine kidney xenotransplant using a human decedent
model, American Journal of Transplantation (2022).
DOI: 10.1111/ajt.16930
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Medical Science