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In an unprecedented medical procedure, physician-scientists at Harvard Medical School at Massachusetts General Hospital have transplanted gene-edited pig kidneys into humans.
Although there are many unknowns about the viability of the newly transplanted organ and the patient’s long-term health, the procedure is made possible in part due to scientific advances made by HMS researchers. This marks a major milestone in the quest to alleviate critical shortages in the United States. Patients with end-stage renal disease.
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The patient, 62-year-old Richard (Rick) Suleiman of Weymouth, Massachusetts, had his kidney removed in a four-hour surgery on March 16. He has type 2 diabetes and high blood pressure, the most common causes of chronic kidney disease. .
Suleiman had previously received a human kidney transplant, but after five years his kidney showed signs of failure and he returned to dialysis with end-stage renal disease, requiring regular hospital visits to manage dialysis complications. became.
“This successful transplant is the culmination of the efforts of thousands of scientists and physicians over several decades. We are honored to have played a key role in this milestone.” Tatsuo KawaiHe is the HMS Professor of Surgery and Director of the Legorreta Center for Clinical Transplant Tolerance in Massachusetts, where he helped guide the transplant team and performed Suleiman’s first kidney transplant in 2018.
“Our hope is that this transplant approach will provide a lifeline to the millions of patients around the world suffering from kidney failure,” he said.
Addressing critical needs
Researchers have been exploring transplantation of organs and tissues from other animals, known as xenotransplantation, as a solution to the global donor organ shortage.transplant Injecting a pig’s heart into a living patient And the Transplanting pig kidneys into brain-dead recipients It made headlines recently.
According to the United Organ Sharing Network, more than 100,000 people are waiting for an organ transplant in the United States, and 17 people die every day while waiting for an organ. According to literature published in , the kidneys are the most commonly needed organ. American Society of Nephrology Journal.
of Estimated 36 million people In the United States, approximately 800,000 people who suffer from chronic kidney disease have end-stage renal disease, or kidney failure, a terminal condition that requires new kidneys or painful long-term dialysis sessions to filter waste products from the blood. and may last for several hours at a time. , several times a week.
Safely transplanting organs from animals to humans requires minimizing the risk that the recipient’s immune system will reject the new organ (also a concern for human organ transplants) and minimizing the risk of infection and other complications. Multiple steps are required to prevent it.
“If it were easy, we’d be doing it by now, but it’s not,” he said. Jolene Madsen, Paul S. Russell/Warner Lambert HMS Professor of Surgery and Director of the MGH Transplant Center. “The barriers to pig xenotransplantation are formidable. The good news is that we were able to overcome that wall.”
scientific progress
The first step involved genetically modifying pig organs to make them more compatible with humans. The kidney used in the new surgery was modified using the gene editing technology CRISPR-Cas9 to:
- Deleting a specific pig gene that produces sugars that our immune systems react to with antibodies.
- Add specific human genes to improve kidney-human compatibility.
- The virus, which is present in the genome of all pigs, known as porcine endogenous retrovirus, is inactivated in the donor pig, eliminating the risk of infection in the recipient.
There were a total of 69 genome edits in the kidney.
The engineered kidneys were provided by eGenesis, a xenotransplant treatment company. Co-founder: HMS geneticist George Church Luhan Yang, former HMS postdoctoral fellow. Over the past five years, Mass General and eGenesis have conducted extensive research and revealed their findings. was announced on Nature October 2023.
The patient, Suleiman, was also given a new monoclonal antibody drug specifically designed to suppress the immune response to pig tissue.
These drugs were provided free of charge by two pharmaceutical companies.
“This collaborative nature between academia and industry is critical to the kind of progress we are sharing today,” he said. Leonard RieraHMS Harold and Ellen Dancer Associate Professor of Surgery and Medical Director of Kidney Transplantation in Massachusetts.
Madsen said the team tested the organ and immunosuppressive drugs extensively in animal models to ensure they had developed the optimal protocol for human application.
Kidneys “immediately turned pink”
Riella, Kawai, and the surgical team led by Riella quickly Nael EliasHMS Assistant Professor of Surgery, Interim Director of Transplant Surgery, and Chief of Kidney Transplant Surgery at Massachusetts General Hospital — said the kidney connection was complete and the new organ “immediately turned pink.” winfred williamsHe is an associate professor at HMS School of Medicine in Massachusetts and Suleiman’s nephrologist.
“They were holding down the ureter and letting the urine come out,” he said. “There was applause in the operating room. It was a great experience.”
About a week after the surgery, Suleiman is recovering well and is expected to be discharged from the hospital soon, according to the Massachusetts General team.
“Today’s real hero is the patient, Mr. Suleiman. The success of this pioneering surgery, once thought unimaginable, is due to his courage and willingness to embark on a journey into unprecedented medical territory. It wouldn’t have been possible without them,” Madsen said.
cautious optimism
The long-term results of transplantation are not yet clear.
“There are so many unknowns,” Riera said. “This is a first for us.”
According to , the surgery will be considered successful if Suleiman does not need to return to dialysis. General FAQ. The researchers hope the pig kidney will improve Suleiman’s health and perhaps buy him time until he can receive another human kidney donation.
“We don’t know yet how many years this kidney can survive, but based on preclinical studies, we’re targeting several years, more than two years,” Kawai said.
Suleiman was approved for experimental procedures under a single FDA Expanded Access Protocol (EAP), often referred to as the Compassionate Use Protocol. These are granted to single patients or groups of patients with serious and life-threatening illnesses or conditions to gain access to experimental treatments or clinical trials when no comparable treatment option or therapy exists. .
Riella led the team in the EAP application. The FDA conducted a rigorous review before issuing approval in late February.
More time as well as more patients will be needed to fully understand the effectiveness of porcine kidney transplantation.
“This is a single patient study with compassionate use,” Williams said. “You will want to take this into a larger clinical trial to confirm that this is a safe method of transplantation. Multicenter-based trials could go a long way in establishing the research validity of this model. Sho.”
For example, it may turn out that pig organs require more gene editing for optimal results.
For now, hopes are growing that kidney xenotransplants may one day save lives and improve quality of life by reducing the need for kidney dialysis.
“Our hope is that dialysis will become obsolete,” Riera said. “We feel strongly that xenotransplantation is also a reasonable option as a bridge. [on the way to receiving a human kidney] Alternatively, it is expected to become a permanent treatment in the future. ”
“At MGH alone, there are more than 1,400 patients on the kidney transplant waiting list,” he said. “Some of these patients, unfortunately, die or become too ill to receive a transplant due to long wait times for dialysis. I believe that xenotransplantation is a promising solution to the organ shortage crisis. I am very confident that there is.”
Focus on health disparities
The researchers are also looking to ensure that xenotransplantation reduces, rather than perpetuating or exacerbating, organ failure and the health disparities associated with organ transplants.
Williams said unequal access to kidney transplants for ethnic minority patients is one of the most intractable problems in the field, and national policy efforts have had limited success over the past 30 years. said.
“The abundant supply of organs due to this technological advancement will ultimately help us achieve health equity and provide all patients in need with the best solution to kidney failure: properly functioning kidneys.” “It could be of great help,” Williams said.
Williams said he admired Suleiman, who is Black, for his “courage in pioneering the transplant field.”
When Williams and his transplant team first proposed a pig kidney transplant, they carefully explained the pros and cons of the procedure. We need a transplant to survive,” Suleiman said in a statement.
Cost is another factor. Williams said the costs associated with Suleiman’s transplant, a first-of-its-kind surgery, would be “huge” and inaccessible to most patients. But if the surgery eventually becomes routine, he says its costs should decrease.
history of success
General Brigham Mass. has a rich history of innovation in organ transplantation.HMS surgeons at Brigham and Women’s Hospital performed the surgery. First successful human organ transplant Today’s mass transplant clinicians and surgeons have nearly 30 years of combined experience in xenograft research.
Elias said Suleiman’s team included doctors, surgeons, scientists, anesthetists and nurses.
“The tireless efforts of our clinicians, researchers, and scientists to improve the lives of current and future transplant patients are at the very heart of academic medicine and what it means to work and provide care at General Brigham Mass. ” said David FM Brown, Director of MGB Academic Medical Center. “I am so grateful to the wonderful staff across the hospital who worked so hard to make this surgery a success, and to the patients for their courage and courage.”
adapted from General Brigham News Release And a press conference.
