Transplantation of gene-edited pig kidneys in decedent human model is “game-changing moment”

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pig kidneys transplantation
Jayme Locke (Credit: UAB)

Peer-reviewed research outlining the successful transplant of genetically modified, clinical-grade pig kidneys into a brain-dead human individual has been published in the American Journal of Transplantation. This publication was recently announced by the University of Alabama at Birmingham (UAB) Marnix E Heersink School of Medicine (Birmingham, USA)—which claims this is the first procedure of its kind and demonstrates how xenotransplantation could address the worldwide shortage of organs.

In the study, UAB researchers tested the first human preclinical model for transplanting genetically modified porcine kidneys into humans. The recipient had two gene-edited pig kidneys transplanted in his abdomen following removal of his native kidneys. The organs were procured from a genetically modified pig at a pathogen-free facility, a UAB press release details.

“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, director of the Comprehensive Transplant Institute in UAB’s Department of Surgery and lead surgeon for the recently published 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 disease.”

Promise offered by xenotransplantation

For the first time—the UAB release claims—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 release adds.

The transplanted kidneys filtered blood, produced urine and were not immediately rejected. The kidneys also remained viable until the study was ended 77 hours after transplant.

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 press release continues. The natural lifespan of a pig is 30 years, and they are easily bred and can have organs of similar size to those in humans.

According to the release, genetically modified pig kidneys have been extensively tested in non-human primates—and evaluations in 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 optimise xenotransplantation outcomes in humans, and lays the foundation for the establishment of a novel preclinical human model for further study.”

Study design

According to UAB, more than 800,000 Americans are currently living with kidney failure—but most never make it to the transplant 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, it continues, transplantation offers a better quality and length of life for the few individuals who can gain access to transplantation.

The recent press release notes that each stage of this decedent xenotransplant study approximated the steps that might be taken in a Phase 1 xenotransplant clinical trial—and was conducted to meet standards directly comparable to those that would apply to an in-human study, mirroring every step of a standard transplant between humans:

  • 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 also included Institutional Review Board and Institutional Animal Care and Use Committee approval, and is supported by biotechnology firm United Therapeutics Corporation, which awarded a grant to UAB to launch the innovative xenotransplantation programme. Revivicor—a subsidiary of United Therapeutics—provided the genetically modified pig that was the source of the investigational xenotransplant kidneys called UKidney.

The UAB announcement goes on to state that this medical breakthrough would not have been possible without 57-year-old registered organ donor Jim Parsons, the patient transplanted with two gene-edited pig kidneys in the study.

“Mr Parsons and his family allowed us to replicate precisely how we would perform this transplant in a living human,” Locke said. “Their powerful contribution will save thousands of lives, and that could begin in the very near future. Mr Parsons’ gift honours 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’.”

Positive findings

Discussing the study further in the American Journal of Transplantation, Locke and colleagues write: “In conclusion, we addressed critical safety and feasibility questions in xenotransplantation by using a novel, preclinical human model under significant regulatory oversight. Our results add significantly to the prior knowledge generated in non-human primate models and suggest that many barriers to xenotransplantation in humans have indeed been surmounted. Importantly, the decedent model identified numerous areas where additional understanding is needed, and all of our results must be interpreted cautiously within the numerous limitations of the model.

“Whether the new knowledge and process gaps identified by our study can be addressed using the decedent model or a combination of in vitro studies with preclinical animal models and even clinical trial data in living humans remains to be determined. Nevertheless, the decedent model has significant potential to propel not only the field of xenotransplantation forward but to answer a multitude of other scientific questions unique to the human condition.”

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