Liver xenotransplantation moves closer to clinical utility

Thousands of people in the United States could benefit from a liver transplant, but the need for donor organs far outstrips the supply. Researchers have long sought ways to expand the donor pool, and one promising approach is xenotransplantation—the transplantation of organs from genetically modified animals, typically pigs.

As leaders in xenotransplantation research, physician-scientists at the Penn Transplant Institute recently demonstrated the feasibility of the approach in humans, showing that pig livers could support metabolic function for several days in patients who had experienced brain death.

As proof of concept for extracorporeal xenogeneic liver support, the experiment was a promising first step toward a clinical role for xenotransplantation, says Abraham Shaked, MD, PhD, Eldridge L. Eliason Professor of Surgery and director of the Penn Transplant Institute at the Perelman School of Medicine. “The field of xenotransplantation is advancing relatively quickly, with real potential for application,” Dr. Shaked says. “As we go forward, we’re figuring out better ways to manage immune suppression and liver function.”

Animal organ transplant

The field of xenotransplantation has focused mostly on hearts and kidneys, obtained from pigs that have been genetically modified to minimize immune rejection by human recipients. Pigs are used because their organs are comparable in size to those of humans. Liver xenotransplantation is substantially more complex than heart and kidney procedures, however, because the liver is a much more functionally complex organ. 

As an illustration of the intricacies involved, Dr. Shaked points to the hundreds of substances produced by the liver, including proteins and lipids, and their wide variety of functional roles in the body—such as synthesizing clotting factors, regulating metabolism, and modulating immune tolerance. Accommodating these many roles has proved to be challenging for liver xenotransplantation. “All of these substances produced by a pig liver are part of the way there, but not all the way,” Dr. Shaked says. “When you look at transplanting a pig liver, immunology is secondary. First, we have to figure out these issues of functional compatibility.”  

For that reason, it’s likely to be some time before pig organs provide long-term support to patients in need of a liver. But in the meantime, pig livers may have a valuable role to play in supporting patients in short-term settings, either within or outside of the body. 

Proof of concept for porcine transplantation 

These approaches are not just theoretical. In the study mentioned above, Dr. Shaked’s team demonstrated the feasibility of short-term xenotransplantation by using genetically modified pig livers to provide extracorporeal liver cross-circulation in humans following brain death. The small study showed that xenogeneic livers could provide effective liver support for up to 84 hours, with minimal immunosuppression. The results were published in Nature Medicine.  

Dr. Shaked and his colleagues are continuing to press forward, aiming to extend the technique to living patients. “Once we figure out a few more things about the system, we hope we can establish a formal clinical trial,” he says.  

Meanwhile, the team is undertaking laboratory studies to improve the functional compatibility of pig livers. In one NIH-funded project, they are investigating the various hematological incompatibilities between pig and human livers. “This exploration may lead to other genetic modifications in the future that will make xenotransplanted organs more functionally compatible,” he says.  

But each additional genetic modification needs to be carefully studied to ensure it doesn’t interfere with the animal’s development and survival, he adds. “The strain of pig we use for xenotransplantation has undergone 69 different genetic modifications to make the organs more compatible with humans. But each new modification could upend the entire system if we don’t do it the right way.”  

Xenotransplantation as a bridge to recovery 

Dr. Shaked is further exploring the use of xenotransplantation as a temporary bridge to recovery in patients with acute liver injury. In acute liver failure from infection, for instance, a porcine liver could support a patient for several days or a week while their own organ recovers. The same approach could be used to support a patient waiting for transplant until a human donor liver becomes available.  

In such cases, the liver doesn’t necessarily need to be surgically implanted into the patient, Dr. Shaked explains. In modern transplant medicine, advanced perfusion devices are used to maintain the function of a harvested donor organ until the time of transplant. Those same devices can maintain pig organs outside the body, connected to the patient by cannulas, to support liver function in the short term—a technique that Dr. Shaked likens to kidney dialysis.  

Xenotransplantation could also support liver function in medium-term settings, thanks to the liver’s unique ability to regenerate. In patients with liver cancer, for example, removing a tumor may leave too little healthy liver tissue to meet the body’s metabolic needs. But a xenotransplant could support liver function for several weeks as the patient’s remaining liver regenerates. Once the organ has recovered enough function, the xenotransplant would be removed. 

Innovating at the Penn Transplant Institute  

While several research groups in the U.S. are studying kidney xenotransplantation, Dr. Shaked’s group is currently the only one in the country pursuing liver xenotransplantation. Given the complexities, he and his colleagues are moving ahead cautiously. “It’s a delicate balance to move the field forward but not to overstep the limits of what we know so far,” he says. “We’re going carefully, step by step.” 

In that stepwise fashion, the Penn Transplant Institute (PTI) is making steady strides toward this new field of transplant medicine. The work is made possible by the deep clinical and research expertise at the PTI, where the liver transplant program is ranked among the best in the nation. 

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Learn more about Liver Transplant at Penn Medicine. To refer a patient or receive consultation from transplant specialists, please call 877-937-7366 or submit a referral through our secure online referral form.