A multidisciplinary team from China performed the world’s first successful genetically modified pig auxiliary liver xenotransplant in a living human.

The liver was able to function and support the patient for 38 days, with no evidence of rejection. However, the patient eventually developed xenotransplant-related thrombotic microangiopathy (xTMA), requiring graft resection, and died on postoperative day 171. 

The case report was published online on October 9 in the Journal of Hepatology.

Pivotal Step Forward

“This case proves that a genetically engineered pig liver can function in a human for an extended period,” lead investigator Beicheng Sun, MD, PhD, Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China, said in a statement.

“It is a pivotal step forward, demonstrating both the promise and the remaining hurdles, particularly regarding coagulation dysregulation and immune complications, that must be overcome,” Sun added. 

The shortage of donors is a major challenge for transplantation. Organs from genetically modified pigs may help bridge the gap. Pig heart and kidneys have been successively transplanted into humans. But transplantation of the liver is more challenging. 

To date, two cases of liver xenotransplantation (one in China and one in the US) have been published — both involving brain-dead individuals.

The current case involved a 71-year-old man with hepatitis B-related cirrhosis and hepatocellular carcinoma in whom tumor resection was anticipated to leave insufficient remnant liver. The patient was not eligible for human liver transplantation.

On compassionate grounds, surgeons implanted an auxiliary graft from a genetically modified pig with 10 gene edits, including xenoantigen knockouts and human transgenes to enhance immune and coagulation compatibility.

For the first 31 days after surgery, no hyperacute or acute rejection, infections, or significant complications were observed, and the patient’s hepatic and renal functions remained stable. 

The graft functioned effectively during this time, producing bile, albumin, and coagulation factors measurable in the patient’s serum, the team reported.

Early postoperative coagulopathy, evidenced by elevated D-dimer and fibrin degradation products, was successfully managed with anticoagulant therapy.

However, on postoperative day 38, the graft was removed following the development of xTMA.

Treatment with the complement inhibitor eculizumab and plasma exchange led to resolution of xTMA. Despite this, the patient later experienced repeated episodes of upper gastrointestinal hemorrhage, which led to his death 171 days after the surgery.

Successful Proof of Concept

The authors of a linked editorial said this case establishes “proof of concept” that genetically modified pig liver grafts can function in humans.

This case report “provides more questions than answers, but that in itself is of immense value. It sets a new benchmark and will become a critical reference for future developments in the field. Whether this is merely a storm in a teacup or the beginning of a new era of bridging strategies in hepatology remains to be seen,” wrote the editorialists, led by Heiner Wedemeyer, MD, Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hanover, Germany.

In a statement from the Spanish Science Media Center, Beatriz Domínguez-Gil, MD, PhD, director, National Transplant Organization, Spain, said this case “represents a new step in the advancement of xenotransplant therapy, which continues to progress in clinical development, but it also highlights the significant obstacles that remain to be overcome, such as the serious complication observed in this patient.” 

Domínguez-Gil said “further work is needed to perfect the genetic modifications carried out, improve the immunosuppression used, and attempt to identify and address any complications that may develop early.”

“Ideally, this should be done in properly designed clinical trials to evaluate their efficacy and safety in the short, medium, and long term. However, these cases allow us to glimpse a future in which xenotransplantation is a clinical reality as a bridge therapy (particularly in the case of the liver) or as a destination therapy,” she noted.

This research had no commercial funding. The authors declared having no relevant conflicts of interest. Wedemeyer is co-editor of the Journal of Hepatology. Disclosure information for Domínguez-Gil was not available.