The world’s second patient has undergone xenotransplantation with a genetically modified pig heart. On September 20, 2023, Lawrence Faucette, 58, received treatment for end-stage heart disease from faculty members of the University of Maryland School of Medicine (UMSOM) at the University of Maryland Medical Center (UMMC). He is currently breathing on his own without any assistive technology, and his heart is beating normally.
Due to his preexisting peripheral vascular disease and complications with internal bleeding, UMMC and several other leading transplant hospitals determined that Faucette was not a good candidate for a conventional transplant with a human heart. Faucette’s heart failure had progressed to the point where death was imminent without the transplant.
On Friday, September 15, the U.S. Food and Drug Administration granted emergency approval for the surgery via its single-patient investigational new drug (IND) “compassionate use” pathway in the hope of saving the patient’s life. This procedure for approval is used when a patient has no other choice and only an experimental medical product—in this case, a genetically altered pig’s heart—to treat a serious or potentially fatal illness.
Beating immune rejection
According to organdonor.gov, there are currently about 110,000 people in the United States on the transplant waiting list, and more than 6,000 people die each year while still waiting. Xenotransplantation, in which organs are harvested from animals and then transplanted into humans, presents its own set of challenges but has the potential to save many lives. In addition to the potential for a xenotransplant to spread a disease from animal to human, there is also the risk that the recipient’s immune system will reject the foreign organ, which can be fatal to the patient.
To prevent the rapid rejection of pig organs by humans due to antibody-mediated rejection, three genes were knocked out in the donor pig. To make the pig’s immune system accept the human heart, scientists inserted six human genes. The donor pig underwent 10 distinct gene edits, including the deletion of a gene that was thought to be responsible for the abnormal growth of heart tissue.
Immunosuppression after a transplant traditionally involves blocking signaling pathways by targeting the CD40 receptor. Studies have shown that blocking CD40L (CD154) stops the co-stimulatory signaling pathways for CD40 and CD11. This may make immunosuppressants more effective and safer by lowering the risk of side effects like lymphopenia, diabetes, high blood pressure, and others.
Faucette is being treated with standard anti-rejection medications and a novel antibody therapy called tegoprubart, developed by Eledon Pharmaceuticals (Nasdaq: ELDN). Tegoprubart is an anti-CD40 Ligand (CD40L) inhibitor still being studied. It stops rejection by blocking a key way immune cells rejecting something talk to each other. In animal models of xenograft rejection, tegoprubart has been shown to extend the time that xenograft organs continue to function significantly.
The lessons learned after the first operation
In January 2022, the pioneering transplant team, widely regarded as the best in cardiac xenotransplantation, performed the first-ever successful xenotransplantation on David Bennett. The UMMC research team spent five years honing the surgical technique on non-human primates before they performed the first surgery on Bennett in 2022. Over more than three decades of xenotransplant research, Muhammad M. Mohiuddin, MD, has published studies showing that a heart from a genetically modified pig can continue to beat when transplanted into the abdomen, even for three years.
Nearly two years have passed since Mr. Bennett received the first genetically modified cardiac xenotransplant, and in that time, faculty scientists at UMSOM have been studying his experience. The results of their initial study were published in the New England Journal of Medicine, and those of their subsequent, more in-depth investigation were published in The Lancet. They showed that the pig heart continued to work normally for weeks after being transplanted into the patient, with no evidence of acute rejection. It is likely that a combination of factors, including Mr. Bennett’s poor health that required him to spend six weeks on a heart-lung bypass machine before his transplant, led to his death from heart failure.
Muhammad M. Mohiuddin, MD, who serves as the program’s scientific director, and Bartley P. Griffith, MD, who surgically transplanted the pig heart into the first and second patients at UMMC, led the procedure. The xenotransplantation laboratory at UMSOM received the genetically modified pig from United Therapeutics Corporation via its Blacksburg, VA-based xenotransplantation subsidiary, Revivicor.
