Category: Transplants

Familial Alzheimer’s Disease Transferred via Bone Marrow Transplant in Mice Experiment

Photo by Mari Lezhava on Unsplash

Familial Alzheimer’s disease can be transferred via bone marrow transplant, researchers show in the journal Stem Cell Reports. When the team transplanted bone marrow stem cells from mice carrying a hereditary version of Alzheimer’s disease into normal lab mice, the recipients developed Alzheimer’s disease – and at an accelerated rate.

The study highlights the role of amyloid that originates outside of the brain in the development of Alzheimer’s disease, which changes the paradigm of Alzheimer’s from being a disease that is exclusively produced in the brain to a more systemic disease. Based on their findings, the researchers say that donors of blood, tissue, organ, and stem cells should be screened for Alzheimer’s disease to prevent its inadvertent transfer during blood product transfusions and cellular therapies.

“This supports the idea that Alzheimer’s is a systemic disease where amyloids that are expressed outside of the brain contribute to central nervous system pathology,” says senior author and immunologist Wilfred Jefferies, of the University of British Columbia. “As we continue to explore this mechanism, Alzheimer’s disease may be the tip of the iceberg and we need to have far better controls and screening of the donors used in blood, organ and tissue transplants as well as in the transfers of human derived stem cells or blood products.”

To test whether a peripheral source of amyloid could contribute to the development of Alzheimer’s in the brain, the researchers transplanted bone marrow containing stem cells from mice carrying a familial version of the disease — a variant of the human amyloid precursor protein (APP) gene, which, when cleaved, misfolded and aggregated, forms the amyloid plaques that are a hallmark of Alzheimer’s disease. They performed transplants into two different strains of recipient mice: APP-knockout mice that lacked an APP gene altogether, and mice that carried a normal APP gene.

In this model of heritable Alzheimer’s disease, mice usually begin developing plaques at 9 to 10 months of age, and behavioural signs of cognitive decline begin to appear at 11 to 12 months of age. Surprisingly, the transplant recipients began showing symptoms of cognitive decline much earlier – at 6 months post-transplant for the APP-knockout mice and at 9 months for the “normal” mice.

“The fact that we could see significant behavioural differences and cognitive decline in the APP-knockouts at 6 months was surprising but also intriguing because it just showed the appearance of the disease that was being accelerated after being transferred,” says first author Chaahat Singh of the University of British Columbia.

In mice, signs of cognitive decline present as an absence of normal fear and a loss of short and long-term memory. Both groups of recipient mice also showed clear molecular and cellular hallmarks of Alzheimer’s disease, including leaky blood-brain barriers and buildup of amyloid in the brain.

Observing the transfer of disease in APP-knockout mice that lacked an APP gene altogether, the team concluded that the mutated gene in the donor cells can cause the disease and observing that recipient animals that carried a normal APP gene are susceptible to the disease suggests that the disease can be transferred to health individuals.

Because the transplanted stem cells were hematopoietic cells, meaning that they could develop into blood and immune cells but not neurons, the researchers’ demonstration of amyloid in the brains of APP knockout mice shows definitively that Alzheimer’s disease can result from amyloid that is produced outside of the central nervous system.

Finally the source of the disease in mice is a human APP gene demonstrating the mutated human gene can transfer the disease in a different species.

In future studies, the researchers plan to test whether transplanting tissues from normal mice to mice with familial Alzheimer’s could mitigate the disease and to test whether the disease is also transferable via other types of transplants or transfusions and to expand the investigation of the transfer of disease between species.

“In this study, we examined bone marrow and stem cells transplantation. However, next it will be important to examine if inadvertent transmission of disease takes place during the application of other forms of cellular therapies, as well as to directly examine the transfer of disease from contaminated sources, independent from cellular mechanisms,” says Jefferies.

Source: Cell Press

World’s First Gene-edited Pig Kidney Transplant into Living Recipient

Surgeons prepare the pig kidney for transplantation. Credit: Massachusetts General Hospital

Massachusetts General Hospital (MGH) has announced the world’s first successful transplant of a genetically-edited pig porcine) kidney into a 62-year-old man living with end-stage kidney disease (ESKD). Surgeons from the Mass General Transplant Center conducted the four-hour-long surgery on Saturday, March 16. The procedure marks a major milestone in the quest to provide more readily available organs to patients. Mass General Brigham is an internationally recognised leader in transplantation services, providing advanced care for a wide spectrum of organ and tissue transplants throughout its renowned academic medical system.

Under the leadership of Leonardo V. Riella, MD, PhD, Medical Director for Kidney Transplantation, Tatsuo Kawai, MD, PhD, Director of the Legorreta Center for Clinical Transplant Tolerance, along with Nahel Elias, MD, Interim Chief of Transplant Surgery and Surgical Director for Kidney Transplantation, a genetically-edited pig kidney with 69 genomic edits was successfully transplanted into a living patient.

Mass General Brigham has a rich history in organ transplant innovation, including the world’s first successful human organ transplant (kidney) performed at Brigham and Women’s Hospital in 1954 and the nation’s first penile transplant, performed at MGH in 2016. Mass General Brigham transplantation programs draw upon the deep, integrated expertise of some of the world’s leading transplant physicians and scientists who collaborate across experienced multidisciplinary teams to advance medicine and improve the lives of patients.

“Mass General Brigham researchers and clinicians are constantly pushing the boundaries of science to transform medicine and solve significant health issues facing our patients in their daily lives,” said Anne Klibanski, MD, President and CEO, Mass General Brigham. “Nearly seven decades after the first successful kidney transplant, our clinicians have once again demonstrated our commitment to provide innovative treatments and help ease the burden of disease for our patients and others around the world.”

“The tireless commitment of our clinicians, researchers and scientists to improving the lives of our transplant patients – both current and future – is at the very heart and soul of academic medicine and what it means to work and provide care at Mass General Brigham,” said David F. M. Brown, MD, President, Academic Medical Centers, Mass General Brigham. “We are so thankful to the incredible staff throughout our hospitals who helped make this surgery a success, and to the patient for his bravery and courage.”

“The success of this transplant is the culmination of efforts by thousands of scientists and physicians over several decades. We are privileged to have played a significant role in this milestone. Our hope is that this transplant approach will offer a lifeline to millions of patients worldwide who are suffering from kidney failure,” Kawai said.

The pig kidney was provided by eGenesis, from a pig donor that was genetically-edited using CRISPR-Cas9 technology to remove harmful pig genes and add certain human genes to improve its compatibility with humans. Additionally, scientists inactivated porcine endogenous retroviruses in the pig donor to eliminate any risk of infection in humans. Over the past five years, MGH and eGenesis have conducted extensive collaborative research, with the findings published in Nature in 2023.

This successful procedure in a living recipient is a historic milestone in the emerging field of xenotransplantation – the transplantation of organs or tissues from one species to another – as a potential solution to the worldwide organ shortage. According to the United Network for Organ Sharing (UNOS), more than 100 000 people in the U.S. await an organ for transplant and 17 people die each day waiting for an organ. A kidney is the most common organ needed for transplant, and end-stage kidney disease rates are estimated to increase 29-68% in the U.S. by 2030, according to literature published in the Journal of the American Society of Nephrology.

The patient, Mr. Richard ‘Rick’ Slayman of Weymouth, Mass., is recovering well at MGH and is expected to be discharged soon.

“The real hero today is the patient, Mr Slayman, as the success of this pioneering surgery, once deemed unimaginable, would not have been possible without his courage and willingness to embark on a journey into uncharted medical territory. As the global medical community celebrates this monumental achievement, Mr Slayman becomes a beacon of hope for countless individuals suffering from end-stage renal disease and opens a new frontier in organ transplantation,” said Joren C. Madsen, MD, DPhil, Director of the MGH Transplant Center.

Mr Slayman said in a statement, “I have been a Mass General Transplant Center patient for 11 years and have the highest level of trust in the doctors, nurses, and clinical staff who have cared for me. When my transplanted kidney began failing in 2023, I again trusted my care team at MGH to meet my goals of not just improving my quality of life but extending it. My nephrologist, Dr Winfred Williams, MD and the Transplant Center team suggested a pig kidney transplant, carefully explaining the pros and cons of this procedure. I saw it not only as a way to help me, but a way to provide hope for the thousands of people who need a transplant to survive. I want to thank everyone at MGH who has cared for me, especially Dr Williams, Dr Kawai, the surgeon who performed my first kidney transplant and now this one, and Dr Riella, who has orchestrated the logistics behind this new transplant. They have supported me during every step of the journey, and I have faith they will continue to do so.”

Mr Slayman, who has been living with Type 2 diabetes and hypertension for many years, previously received a kidney transplant from a human deceased donor in December 2018, performed at MGH by Kawai, after being on dialysis seven years prior. The transplanted kidney showed signs of failure approximately five years later and Mr Slayman resumed dialysis in May 2023. Since resuming dialysis, he encountered recurrent dialysis vascular access complications requiring visits to the hospital every two weeks for de-clotting and surgical revisions, significantly impacting his quality of life and a common problem among dialysis patients.

“The continued success of this groundbreaking kidney transplant represents a true milestone in the field of transplantation. It also represents a potential breakthrough in solving one of the more intractable problems in our field, that being unequal access for ethnic minority patients to the opportunity for kidney transplants due to the extreme donor organ shortage and other system-based barriers. This health disparity has been the target of many national policy initiatives for over 30 years, with only limited success. An abundant supply of organs resulting from this technological advance may go far to finally achieve health equity and offer the best solution to kidney failure – a well-functioning kidney – to all patients in need. I commend Mr Slayman, who has been my patient for many years, for his courageousness in becoming a trailblazer in the field of transplantation,” Williams said.

The procedure was performed under a single FDA Expanded Access Protocol (EAP) – known as compassionate use – granted to a single patient or group of patients with serious, life-threatening illnesses or conditions to gain access to experimental treatments or trials when no comparable treatment options or therapies exist. Mr. Slayman also received infusion of novel immunosuppressant drugs, tegoprubart, provided by Eledon Pharmaceuticals, Inc., and ravulizumab, provided by Alexion Pharmaceuticals, Inc.

Source: Massachusetts General Hospital

Surgeons Perform World’s First Whole-eye & Partial-face Transplant

Dr Rodrigueze and Aaron James. Credit: NYU Langone Health

A surgical team from NYU Langone Health performed the world’s first whole-eye and partial-face transplant for a 46-year-old military veteran from Arkansas who survived a work-related high-voltage electrical accident. The surgery included transplanting the entire left eye and a portion of the face from a single donor, making this the first-ever human whole-eye transplant in medical history and the only successful combined transplant case of its kind.

While it is still unknown whether he will regain sight, since the May 2023 procedure, the transplanted left eye has shown remarkable signs of health, including direct blood flow to the retina. Although many questions remain in a case with no precedence, this groundbreaking achievement opens new possibilities for future advancements in vision therapies and related medical fields.

About the Procedure

The May 27 surgery lasted approximately 21 hours and included a team of more than 140 surgeons, nurses, and other healthcare professionals, led by Eduardo D. Rodriguez, MD, DDS, director of the Face Transplant Program, the Helen L. Kimmel Professor of Reconstructive Plastic Surgery, and chair of the Hansjörg Wyss Department of Plastic Surgery at NYU Langone.

The recipient, Aaron James of Hot Springs, Arkansas, survived a deadly 7200-volt electric shock while working as a high-voltage lineman in June 2021, when his face accidentally touched a live wire. Despite multiple reconstructive surgeries, James had extensive injuries – including the loss of his left eye, his dominant left arm from above the elbow, his entire nose and lips, front teeth, left cheek area, and chin down to the bone.

“Aaron has been extremely motivated to regain the function and independence he lost after his injury. We couldn’t have asked for a more perfect patient,” said Dr Rodriguez. “We owe much of our success in this monumental endeavour to the exceptional institutional support we receive at NYU Langone and the unwavering dedication of our world-class team in delivering the highest level of care to our patient. This achievement demonstrates our capacity to embrace the most difficult challenges and drive continuous advancements in the field of transplantation and beyond.”

The NYU Langone team was introduced to James’ case just two months after his injury, allowing guidance during the early-phase reconstructions with specialists at a Texas medical centre where he was receiving care. The possibility of a face transplant was discussed over the next year, and an initial evaluation for the transplant took place one year following the initial injury in June 2022.

When Texas surgeons were forced to remove James’ left eye after injury due to severe pain, Dr. Rodriguez and his team recommended that the optic nerve be cut as close to the eyeball as possible, to preserve as much nerve length to maximize reconstructive options, including the hope of a potential transplant later. This began the discussion on the possibility of including an eye with the face, something that has never been attempted before.

NYU Langone’s multidisciplinary team, Dr Rodriguez, and the James family collectively made the decision to move ahead with a whole-eye transplant in combination with the face – understanding that at best it may only provide cosmetic benefits but leave many unknowns.

“Given Aaron needed a face transplant and will be taking immunosuppressive drugs regardless, the risk versus reward ratio of transplanting the eye was very low. Despite the eye being successfully transplanted, from a cosmetic standpoint, it would still be a remarkable achievement,” said Dr. Rodriguez.

This is the fifth face transplant performed under the leadership of Dr. Rodriguez and the first known whole-eye transplant in existence. “The mere fact that we’ve accomplished the first successful whole-eye transplant with a face is a tremendous feat many have long thought was not possible,” added Dr. Rodriguez. “We’ve made one major step forward and have paved the way for the next chapter to restore vision.”

One of the Shortest Wait Times for a Donor—Three Months

Once James’ case cleared all approvals within NYU Langone, he was officially listed as a potential recipient in February 2023 with the United Network for Organ Sharing (UNOS), the private, nonprofit organization that manages the nation’s organ transplant system.

Locally, the effort to find a donor for James was led by LiveOnNY, the organ procurement organization for the greater New York metropolitan area. In May 2023, just three months after James was listed for organ donation, coordinators from LiveOnNY identified a potential donor at another hospital in New York City. After a series of donor evaluations – including tests to determine if the eye was healthy and viable, led by Vaidehi S. Dedania, MD, retina specialist in the Department of Ophthalmology at NYU Langone – he was deemed an ideal donor. The total time from injury to transplant was a little under two years.

“The donor hero was a young man in his 30s who came from a family that strongly supports organ donation. He, in support by his family, generously donated tissues leading to this successful face and eye transplant, but also saved three other individuals between the ages of 20 and 70, donating his kidneys, liver, and pancreas,” said Leonard Achan, RN, MA, ANP, president and CEO of LiveOnNY. “LiveOnNY is proud to have collaborated with such a distinctive team of medical professionals at NYU Langone. This act of grace and innovative surgical procedure will have a multigenerational impact on all the recipients and their loved ones.”

A Question of Nerve

While corneal transplants have become relatively common, with thousands performed in the United States each year, successful whole-eye transplants to restore vision have remained elusive due to the complex nature of the eye and the challenges associated with nerve regeneration, immune rejection, and retinal blood flow.

The human eye is intricately connected to the brain through the optic nerve, part of the central nervous system and responsible for transmitting visual information to the brain. Reestablishing these nerve connections successfully is a fundamental requirement for a whole-eye transplant to restore vision and one of the biggest challenges.

Dr Rodriguez, in collaboration with the team at NYU Langone’s Transplantation and Cellular Therapy Center, part of the Blood and Marrow Transplant Program at Perlmutter Cancer Center, made the decision to combine the donor eye with donor bone marrow–derived adult stem cells. Bone marrow is a sponge-like tissue found inside the large bones in the body. Adult stem cells that are transplanted can work as a replacement therapy and natural repair crew, dividing again and again to create heathy cells that replace the damaged or dysfunctional elements.

“This is the first attempt of injecting adult stem cells into a human optic nerve during a transplant in the hopes of enhancing nerve regeneration,” said Samer Al-Homsi, MD, MBA, executive director of the Transplantation and Cellular Therapy Center and professor in the Department of Medicine at NYU Langone. “We chose to use CD34-positive stem cells which have been shown to harbor the potential to replace damaged cells and neuroprotective properties.”

During the transplant, bone marrow that was harvested from the donor’s vertebrae and processed preoperatively to isolate the CD34-positive stem cells was brought into the operating room (OR) and injected at the optic nerve connection of the recipient.

“We have now demonstrated that the procedure is safe and potentially efficacious, but we need time to determine if this step plays a role in enhancing the chance of sight restoration and if there’s anything further that can be done in the future to optimize the procedure,” added Dr Al-Homsi.

Innovations in Face Transplant Technology

Through collaboration with Depuy Synthes, the Orthopedics Company of Johnson & Johnson, and Materialise, state-of-the-art technology played a pivotal role in both presurgical planning and the actual surgery. Cutting-edge three-dimensional (3D) computer surgical planning, along with patient-specific 3D cutting guides, enabled precise alignment of bones and optimal placement of implantable plates and screws. This meticulous approach fit the grafted partial face and whole left eye onto James.

The successful surgery took place in NYU Langone’s Kimmel Pavilion, where expansive ORs enabled two highly skilled surgical teams to simultaneously operate in both the donor and recipient rooms. The surgical teams adhered to a carefully planned timetable – which was rehearsed many times over the last year – as the team proceeded with the transplantation and reconstruction process, seamlessly integrating the donor’s face and eye onto James as quickly as possible to ensure the optimal outcome. Dr. Rodriguez and his surgical team of 7 – and OR team of 80 – transplanted the following:

  • partial face, including the nose, left upper and lower eyelids, left eyebrow, upper and lower lips, and underlying skull, cheek, nasal and chin bone segments, with all of the tissues below the right eye including the underlying muscles, blood vessels, and nerves
  • left whole eye and socket including the orbital bones and all surrounding eye tissues including the optic nerve

As they do in all transplant operations, the surgeons sought to complete the procedure as quickly as possible to limit the ischemia time, or the amount of time the donated tissue is not receiving a blood supply.

“The progress we’ve seen with the eye is exceptional, especially considering that we have a viable cornea paired with a retina showing great blood flow five months after the procedure. This far exceeds our initial expectations, given our initial hope was that the eye would survive at least 90 days,” said Bruce E. Gelb, MD, a transplant surgeon at the NYU Langone Transplant Institute and vice chair of quality in the Department of Surgery. “We will continue to monitor, and I am excited to see what else we may learn over time.”

Dr. Rodriguez has since performed a less extensive follow-up surgery for James to optimise his functional and aesthetic outcome. James plans to have orthodontic treatment and dental rehabilitation in the coming months.

“Beyond the eye, the quality of Aaron’s results from the face transplant is special. You would never think he underwent such a procedure so recently. He looks great,” said Dr. Rodriguez.

The NYU Langone team has set the standard in the field of face transplants for eliminating and avoiding early rejection episodes as well as the frequency of rejections using a unique immunosuppression regimen.

As in previous face transplants, Dr. Rodriguez and his team collaborated with NYU’s advanced 3D media services center, LaGuardia Studio, to create a 3D-printed replacement of the donor’s face to restore the integrity of the donor’s identity after the organs were removed to return to his family. Traditionally, a molded, hand-painted silicone mask had been used. There are few printers in the world like the one at LaGuardia, which prints with 60,000 colors.

A Determined Patient Focused on Healing

Following the surgery, James spent just 17 days in the intensive care unit at NYU Langone, one of the shortest recoveries among Dr. Rodriguez’s face transplant recipients. He was discharged on July 6 to a nearby apartment. From there, he continued outpatient rehabilitation including physical, occupational, and speech therapy.

James continues to remain positive and eternally grateful to regain many elements of life he lost after the 2021 injury, especially the ability to taste, smell, and eat solid foods. On September 14, he returned home to Arkansas with his wife, Meagan, and daughter, Allie. James comes back to New York City monthly for follow-up appointments. He has the option to return to work as a safety manager for high-voltage line workers in the future.

“I’m grateful beyond words for the donor and his family, who have given me a second chance at life during their own time of great difficulty. I hope the family finds solace in knowing that part of the donor lives on with me,” said James. “I will also forever be thankful to Dr. Rodriguez and his team for changing my life. My family and I wouldn’t have been able to navigate this difficult journey without their expertise and support. Our hope is that my story can serve as inspiration for those facing severe facial and ocular injuries.”

James is looking forward to spending the upcoming Thanksgiving holiday with his family, getting to enjoy eating a holiday meal for the first time since his injury.

Seeing the Future

While James’ vision in his native right eye is intact, the transplanted left eye does not currently have any sight. However, over the last six months, his eye has shown remarkable signs of health in other regards based on various clinical tests that measure outcome.

Dr. Rodriguez, Dr. Dedania, and a multidisciplinary team of world-renowned researcher scientists and clinicians – including leaders in neurology, ophthalmology, radiology, and neuroradiology – continue to convene and discuss questions that remain related to the eye and ways to measure any indications toward sight restoration.

“What we’re witnessing now is not something we ever expected or thought we’d see,” said Dr. Dedania, who runs regular tests for James in relation to his eyes. “The first step is having an intact eyeball, a lot of things could come after that; this is a first in the world, so we are really learning as we go.”

James will continue to have various clinical tests on the left transplanted eye, including electroretinography, a test that measures the electrical response of the retina to light.

“This is certainly one extraordinary step in the right direction,” said Steven L. Galetta, MD, renowned neuro-ophthalmologist and the Philip J. Moskowitz, MD, Professor and Chair of Neurology at NYU Langone. “We’re now crossing into the frontier of the central nervous system. Whatever happens next allows the opportunity for various methods to try to enhance the remaining aspects of the retina, whether it be through growth factors, stem cells, or a device that can pick up the signals and then bypass things along that optic nerve pathway. I’m looking forward to further advancements from this case in collaboration with the very talented minds that made it happen here at NYU Langone.”

Pig-to-human Kidney Xenotransplant is the Longest Successful One Yet

Photo by Natanael Melchor on Unsplash

Surgeons at NYU Langone Health have transplanted a genetically engineered pig kidney that continues to function well after 32 days in a man declared dead by neurologic criteria and maintained with a beating heart on ventilator support. This represents the longest period that a gene-edited pig kidney has functioned in a human, and the latest step toward the advent of an alternate, sustainable supply of organs for transplant.

Led by Robert Montgomery, MD, DPhil, the procedure was performed on July 24, 2023 and marks the fifth xenotransplant performed at NYU Langone. Observation is ongoing and the study will continue through mid-September 2023.

“This work demonstrates a pig kidney – with only one genetic modification and without experimental medications or devices – can replace the function of a human kidney for at least 32 days without being rejected,” said Dr Montgomery, who had previously performed the world’s first genetically modified pig kidney transplant into a human decedent in 2021.

Removing single troublesome gene

The first hurdle to overcome in xenotransplants is preventing so-called hyperacute rejection, which typically occurs just minutes after an animal organ is connected to the human circulatory system. By “knocking out” the gene that encodes the biomolecule known as alpha-gal, responsible for a rapid antibody-mediated rejection of pig organs by humans, immediate rejection has been avoided in all five xenotransplants at NYU Langone. Additionally, the pig’s thymus gland, which is responsible for educating the immune system, was embedded underneath the outer layer of the kidney to stave off novel, delayed immune responses. The combination of modifications has been shown to prevent rejection of the organ while preserving kidney function.

To ensure the body’s kidney function was sustained solely by the pig kidney, both of the transplant recipient’s native kidneys were surgically removed. One pig kidney was then transplanted and started producing urine immediately without any signs of hyperacute rejection. During the observation phase, intensive care clinical staff maintained the decedent on support while the pig kidney’s performance was monitored and sampled with weekly biopsies. Levels of creatinine, a bodily waste product found in the blood and an indicator of kidney function, were in the optimal range during the length of the study, and there was no evidence on biopsy of rejection.

The surgery was the latest in a larger study approved by a specific research ethics oversight board at NYU Langone and was performed after consultation with the New York State Department of Health. This important research, which study leaders say could save many lives in the future, was made possible by the family of a 57-year-old male who elected to donate his body after a brain death declaration and a circumstance in which his organs or tissues were not suitable for transplant.

A big leap toward a new organ source

“There are simply not enough organs available for everyone who needs one,” said Dr Montgomery, who received a hepatitis C-positive heart transplant himself in 2018. “Too many people are dying because of the lack of available organs, and I strongly believe xenotransplantation is a viable way to change that.”

The kidney and thymus gland used in this procedure were procured from a GalSafeTM pig, an animal engineered by Revivicor, Inc., a subsidiary of United Therapeutics Corporation. In December 2020, the U.S. Food and Drug Administration (FDA) approved the GalSafe pig as a potential source for human therapeutics as well as a food source for people with alpha-gal syndrome, a meat allergy caused by a tick bite.

Less may be more

While previous genetically engineered pig organ transplants have incorporated up to 10 genetic modifications, this latest study shows that a single-gene knockout pig kidney can still perform optimally for at least 32 days without rejection.

“We’ve now gathered more evidence to show that, at least in kidneys, just eliminating the gene that triggers a hyperacute rejection may be enough along with clinically approved immunosuppressive drugs to successfully manage the transplant in a human for optimal performance – potentially in the long-term,” said Dr Montgomery.

The NYU Langone team used standard transplant immunosuppression medications combined with enhanced screening of porcine cytomegalovirus (pCMV) in the donor pig to ensure safety. Recent studies have shown pCMV may affect organ performance and potentially trigger organ failure. No pCMV was detected after 32 days, and close surveillance of porcine endogenous retrovirus (PERV), along with six other viruses of interest, was performed.

Next steps

Monitoring of the pig kidney recipient will continue for another month with permission from the family, ethics committee approval and continued support from United Therapeutics. The additional data from the next several weeks will be analyzed further to develop a deeper understanding of this unique medical advance.

“We think using a pig already deemed safe by the FDA in combination with what we have found in our xenotransplantation research so far, gets us closer to the clinical trial phase,” said Dr Montgomery. “We know this has the potential to save thousands of lives, but we want to ensure the utmost safety and care as we move forward.”

Source: NYU Langone Health

Lessons Learnt From First Human Transplant of Genetically Modified Pig Heart

Photo by Natanael Melchor on Unsplash

A new study published 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 in January 2022.

The patient, 57-year-old David Bennett, 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 extensively studying the physiologic processes that led to the heart failure to identify what needs to be prevented in future transplants to improve the odds of 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, but the experimental procedure was authorised by the US Food and Drug Administration under compassionate use.

“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.

“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 utilise 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.”

Source:

Better Transplant Outcomes from Slightly Warmer Donor Lungs

Photo by Robina Weermeijer on Unsplash

Storing donor lungs for transplant at 10°C markedly increases the length of time the organ can live outside the body, according to results of a trial were published in the New England​ Journal of Medicine Evidence. These findings will help reduce the strain on hospitals, reduce waitlists and possibly eliminate the need to bump other surgeries for a lung transplant.

The multicentre, non-randomised clinical trial study of 70 patients demonstrated that donor lungs remained healthy and viable for transplant up to four times longer compared to storage at the current standard of ice cooler preservation of around 4°C. The study was led by a team of scientists at the Toronto Lung Transplant Program in UHN’s Ajmera Transplant Centre.

“The clinical impact of this study is huge,” says lead author Dr Marcelo Cypel, Surgical Director of the Ajmera Transplant Centre and a surgeon within UHN’s Sprott Department of Surgery.

“It’s a paradigm shift for the practice of lung transplant.​ I have no doubt that this will become the gold standard practice of lung preservation for the foreseeable future.”

Lungs available for transplant are currently limited by the length of time a donor organ can be kept viable. Increasing storage time allows for viable donor lungs to come from greater distances, increasing the potential for greater numbers of lungs becoming available for transplant and overcoming many of the hurdles around transplant logistics.

“In transplant, we still see a critical shortage of organs and people dying on the waitlist because there are not enough lungs to be transplanted,” says Dr Cypel, who is also a professor in the Division of Thoracic Surgery, Department of Surgery at the University of Toronto.

“It’s a great accomplishment to see that our research is now having an impact, and that we can actually have more cases done at our centre, with continued outstanding clinical results.

“Better organ preservation also means better outcomes for patients.”

Transplant surgeries could become planned procedures

The trial took place over 18 months at UHN’s Toronto General Hospital, the Medical University of Vienna, and Hospital Universitario Puerta de Hierro-Majadahonda in Madrid.

“The ability to extend the lifespan of the donor organ poses several advantages,” says study first author Dr Aadil Ali, adjunct scientist at the Toronto General Hospital Research Institute.

“Ultimately, these advantages will allow for more lungs to be utilised across farther geographies and the ability to improve recipient outcomes by converting lung transplantation into a planned rather than urgent procedure.”

Some advantages of this new 10°C standard for lung storage include the potential to reduce or eliminate the 24/7 schedule and urgency of lung transplant procedures. By increasing the length of time donor lungs are viable, transplant surgeries could become planned procedures, which avoids bumping scheduled surgeries and overnight transplantation.

The study also suggests the new preservation temperature will allow more time to optimise immunologic matching between donor and recipients, and the possibility of performing lung transplantation in a semi-elective rather than urgent fashion.

For more on the study, watch Dr Marcelo Cypel’s presentation of findings at a recent American Association for Thoracic Surgery event.

Also, watch a video with Drs Cypel and Ali discussing the foundational work leading to this breakthrough.

Source: University Health Network

Groote Schuur Performs Africa’s First ABO-incompatible Kidney Transplant

Anatomic model of a kidney
Photo by Robina Weermeijer on Unsplash

Eyewitness News reports that doctors at Groote Schuur Hospital have successfully performed Africa’s first incompatible kidney transplant. Known as ABO-incompatible (ABOi) transplants, these procedures are done when the donor’s blood type does not match the recipient’s – once a major contraindication.

The patient, a 35 year old woman named Chervon Meyer, received a kidney donation from her brother. She had been on dialysis for 10 years,

Over half a century ago, Groote Schuur had its mark on history with the world’s first human heart transplant led by Dr Christiaan Barnard.

Incompatible living kidney transplants have long been contraindicated because of the presence of isohaemagglutinins, natural antibodies reacting with non-self ABO antigens. Due to the growing demand for transplant organs, incompatible donations were investigated in order to expand the pool of possible donors. This has changed with the development of new desensitisation regimens over the past decades. These include immunoadsorption and plasmapheresis and the immunosuppressive protocol.

The improvements have been so great that, despite a lack of randomised trials, recent meta analysis found that there is no difference in terms of graft and patient’s survival between ABOi and ABO compatible kidney transplant, even in the long term.

As nephrologist Dr Zunaid Barday explains, this procedure made use of a Glycosorb filter which reduced many of the risks associated with desensitisation, such as plasma exchange weakening the immune system. It works by binding anti-A and anti-B antibodies, reducing their levels in blood plasma. While expensive, the filter is a much cheaper alternative in the long run compared to years of dialysis.

Source: Eyewitness News

Is Protein Restriction the Best Option after Kidney Transplant?

Anatomic model of a kidney
Photo by Robina Weermeijer on Unsplash

Scientists at Osaka Metropolitan University have challenged the conventional wisdom that low protein intake is essential for kidney disease patients with their recent study on the relationship between protein intake and skeletal muscle mass in kidney transplant recipients. Their findings were published in Clinical Nutrition.

Chronic kidney disease patients are known to have induced sarcopenia due to chronic inflammation, hypercatabolism, decreased nutrient intake, and decreased physical activity associated with impaired kidney function. A successful kidney transplantation is able to correct or improve many of those physiological and metabolic abnormalities, with the transplant recipients increasing skeletal muscle mass after receiving their new kidney. Since excessive protein intake worsens kidney function, it is commonly believed that patients with chronic kidney disease, including kidney transplant recipients, should limit protein intake to protect their kidneys. On the other hand, it has been suggested that severe protein restriction may worsen sarcopenia and adversely affect prognosis.

Since nutrition and exercise therapy are recommended to improve sarcopenia, protein intake is suspected to relate to recovery of skeletal muscle mass after kidney transplantation. However, few studies have examined the relationship between skeletal muscle mass and protein intake in kidney transplant recipients.

In order to fill this knowledge gap, a research group led by Drs Akihiro Kosoku and Tomoaki Iwai, and Professor Junji Uchida at Osaka Metropolitan University followed 64 kidney transplant recipients for 12 months after their procedure. They investigated the relationship between changes in skeletal muscle mass, as measured by bioelectrical impedance analysis, and protein intake from urine sample. The results showed that changes in skeletal muscle mass during this period were positively correlated with protein intake, and that insufficient protein intake resulted in decreased muscle mass.

Drs Iwai and Kosoku commented, “To improve the life expectancy of kidney transplant recipients, further research is needed to clarify the optimal protein intake to prevent either deterioration in kidney function or sarcopenia. We hope that nutritional guidance, including protein intake, will lead to improved life expectancy and prognosis.”

Source: Osaka Metropolitan University

Excellent Outcomes for Shrinking Liver Cancer Tumours Before Transplant

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Shrinking liver cancer tumours in order to allow the patient to qualify for a liver transplant leads to excellent 10-year post-transplant outcomes, according to the findings of a new study published in JAMA Surgery. The results validate current US policies around transplant eligibility.

Selection of patients with hepatocellular carcinoma (HCC), the most common form of liver cancer, for transplant has been guided for more than two decades by standards known as the Milan criteria. The Milan criteria state that transplantation should be performed in those with a single tumour of 5cm or less in diameter or three tumours that are each 3cm or less in diameter, have no macrovascular invasion, and no metastasis. Over time, the rising incidence of HCC and mortality rates in the United States have led to refinements to the selection policy, shifting the focus to guidelines that also incorporate tumour biology, response to bridging therapies, and waiting times for patients within and beyond the Milan criteria.

One aspect of the current criteria is known as downstaging: the process of applying liver directed therapy to tumours too big for the Milan criteria with the hope of reducing them to the suggested size. Downstaging is now an option in selecting suitable liver transplant candidates with initial tumors that exceed the criteria. However, liver cancer can recur after transplantation, either within or outside the liver. The treatment options of patients who have recurrence post transplantation is limited and prognosis is poor.

In this cohort study, a retrospective multicentre analysis of prospectively collected data was conducted for 2645 adults who had undergone liver transplant for HCC at five centres between January 2001 and December 2015. The outcomes of 341 patients whose disease was downstaged to fit within the Milan criteria were compared with those in 2122 patients whose disease always fit within the criteria and 182 patients whose disease was not downstaged.

The 10-year post-transplant survival and recurrence rates were, respectively, 52.1% and 20.6% among those whose disease was downstaged; 61.5% and 13.3% in those always within the criteria; and 43.3% and 41.1% in those whose disease was not downstaged.

“Our study validates national policy on downstaging prior to transplantation and shows the clear utility benefit for transplantation prioritisation decision-making,” said Parissa Tabrizian, MD, co-lead author on the study. “These results can increase the level of recommendations for the downstaging policy on a global basis. It also demonstrates that surgical management of HCC recurrence after transplantation is associated with improved survival in well-selected patients and should be pursued. The study also supports expanding the policy of downstaging applied to guidelines in Europe and Asia.”

“Our study represents a solid confirmation that HCC patients effectively downstaged to Milan criteria have an outstanding median survival of 10 years, thus providing the rationale to adopt this policy on a global basis,” said Josep Llovet, MD, PhD, co-lead author on the study. “With this study clinical practice guidelines of management of HCC can recommend our approach with an acceptable level of evidence.”

Source: The Mount Sinai Hospital

Paediatric Kidney Transplants without Immunosuppressive Drugs

Anatomic model of a kidney
Photo by Robina Weermeijer on Unsplash

Stanford Medicine physicians have developed a way to provide paediatric kidney transplants without immunosuppressive drugs. Their key innovation is a safe method to transplant the donor’s immune system to the patient before surgeons implant the kidney.

The medical team has dubbed the two-transplant combination a “dual immune/solid organ transplant,” or DISOT. The first three DISOT cases, all performed at Lucile Packard Children’s Hospital Stanford were described in the New England Journal of Medicine, accompanied by an an editorial about the research.

The Stanford innovation removes the possibility that the recipient will experience immune rejection of their transplanted organ, the most common reason for a second organ transplant The new procedure also rids recipients of the substantial side effects of a lifetime of immune-suppressing medications, including increased risks for cancer, diabetes, infections and hypertension.

“Safely freeing patients from lifelong immunosuppression after a kidney transplant is possible.”

Alice Bertaina, MD, PhD, report’s lead author, associate professor of paediatrics, Stanford University

The first three DISOT patients were children with a rare immune disease, but the team is expanding the types of patients who could benefit. The protocol received FDA approval on May 27, 2022, for treating patients with a variety of conditions that affect the kidneys. Dr Bertaina anticipates that the protocol will eventually be available to many people needing kidney transplants, starting with children and young adults, and later expanding to older adults. The researchers also plan to investigate DISOT’s utility for other types of solid-organ transplants.

The scientific innovation from Dr Bertaina’s team has another important benefit: It enables safe transplantation between a donor and recipient whose immune systems are genetically half-matched, meaning children can receive stem cell and kidney donations from a parent.

The advance is especially meaningful for Jessica and Kyle Davenport of Muscle Shoals, Alabama. Their two children, both born with a rare and potentially deadly immune disease, are among the first recipients of DISOT: 8-year-old Kruz received transplants from Jessica, while his 7-year-old sister, Paizlee, received transplants from Kyle.

“They’ve healed and recovered, and are doing things we never thought would be possible,” said Jessica Davenport. After years of helping Kruz and Paizlee cope with severe immune deficiency and its attendant infection riskk as well as kidney dialysis, she and her husband are thrilled that their children have more normal lives.

The idea of transplanting a patient with their organ donor’s immune system has been around for decades, but it has been difficult to implement. Transplants of stem cells from bone marrow provide the patient with a genetically new immune system, as some of the bone marrow stem cells mature into immune cells in the blood. First developed for people with blood cancers, stem cell transplants carry the risk of the new immune cells attacking the recipient’s body, a potentially lethal complication called graft-versus-host disease.

Source: Stanford Medicine