The first peer-reviewed study describing the successful transplant of genetically modified, clinical-grade pig kidneys into a brain-dead human individual, replacing the recipient’s native kidneys, has been published. These encouraging findings show how xenotransplantation could help to address the global organ shortage crisis.
The Marnix E. Heersink School of Medicine at the University of Alabama at Birmingham has published the first peer-reviewed study describing the successful transplant of genetically modified, clinical-grade pig kidneys into a brain-dead human individual, replacing the recipient’s native kidneys. These encouraging findings show how xenotransplantation could help to address the global 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.”
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.
Jayme Locke
The pig kidneys transplanted were taken for the first time from pigs that had been genetically modified with 10 key gene edits that may make the kidneys suitable for transplant into humans. This procedure demonstrates the procedure’s long-term viability and how such a transplant might work in the real world. The transplanted kidneys filtered blood, produced urine, and, most importantly, were not rejected right away. The kidneys were still viable 77 hours after transplant when the study ended.
“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 enabled pig-to-human organ transplants, which could help thousands of people suffering from organ failure, disease, or injury. A pig has a natural lifespan of 30 years, is easily bred, and can have organs the size of humans.
Non-human primates have been extensively tested with genetically modified pig kidneys. In addition to testing in nonhuman 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 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™.
About the study
Given that more than 800,000 Americans suffer from kidney failure, the peer-reviewed study is both ambitious and significant. Most never make it to the waiting list, and there are far too few human organs available to make a dent in that figure. Although dialysis can keep people alive for a while, transplantation provides a better quality of life and a longer life for the few people who qualify. Each stage of this decedent xenotransplant study was designed to approximate the steps that would be taken in a Phase I xenotransplant clinical trial:
- The kidneys were extracted from a pathogen-free, surgically clean donor pig. The kidneys were then stored, transported, and prepared for implantation in the same way that human kidneys are.
- The brain-dead recipient and donor animals were subjected to a crossmatch compatibility test prior to surgery to determine whether the genetically modified pig kidney and its intended recipient were a good tissue match. Every human-to-human kidney transplant requires a crossmatch; however, this pig-to-human tissue-match test developed at UAB was the first to validate a prospective crossmatch 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 designed to meet standards that are directly comparable to those that would apply to a Phase I human clinical trial, mirroring every step of a standard human transplant. It included approval from the Institutional Review Board and the Institutional Animal Care and Use Committee, tissue compatibility confirmation before beginning the operations, using standard human-to-human transplant procedures to remove, preserve, transport, and transplant the kidneys into a human, and administering standard immunosuppression therapy to the recipient.
The critical need for other organ donation options
According to the National Institute of Diabetes and Digestive and Kidney Diseases, kidney disease kills more people each year than breast or prostate cancer. Despite being the gold standard treatment for end-stage kidney disease, fewer than 25,000 kidney transplants are performed in the United States each year, and 240 Americans on dialysis die every day. Many of these deaths could be avoided if there were an unlimited supply of kidneys available for transplant.
The wait for a deceased donor kidney can last up to five years, and in many states, the wait is closer to ten. Every year, nearly 5,000 people die while waiting for a kidney transplant.
