The Holy Grail Of Using Pig Organs To Save Lives Is Making Progress
Renowned liver transplant physician Robert Brown has a quip about xenotransplantation, the tricky science of making animal organs compatible with humans. The field’s long-sought objective is to offer a profoundly needed solution for the hundreds of thousands of patients around the world who need an organ.
“We used to joke that xenotransplantation was five to ten years away from reality and always will be,” Dr. Brown says. He recalled a trial he ran over two decades ago with cryopreserved pig liver cells, which carried a hint of working in humans, but lacked enough cell mass to be effective. Given the strides in technology over the last twenty years, he said, “Now it may really be on the horizon.”
Today we are on the cusp of first-in-human trials, and the anticipation in the field is palpable.
“I am super optimistic and excited,” says Dr. Robert Montgomery, a leading transplant surgeon at NYU Langone Health. “I think it is the answer to the organ shortage. It’s the closest thing we have in hand. Right behind it is bioartificial organs, and someday that will be an important source of organs as well, but we’re not quite as far along with it.”
How We Got Here
Attempts at xenotransplantation date back hundreds of years in the medical literature, though the concept was explored as early as 600 BC. Not surprisingly, those attempts failed. In the 1960s through the 1990s, with the advent of immunosuppressant drugs, several dozen xenotransplants were tried using primate kidneys and hearts; patients’ survival ranged from minutes to 70 days.
It eventually became clear that immunosuppressant drugs alone were not enough for long-term patient survival. Adult pigs also became the donor of choice instead of primates, who are closer to us genetically, because of their size match along with their shorter time to maturity and ability to produce more offspring in shorter pregnancies.
But in 1994, scientists discovered endogenous retroviruses (PERVs) that are embedded in the porcine genome and pose the potential risk of infection for human recipients. Many countries put limits on xenotransplants until a plan could be demonstrated for safety and efficacy. Early forms of genetic modification in the 1990s offered the tantalizing possibility of modifying porcine DNA to make it compatible with the human immune system, but the technology wasn’t yet up to the task.
Then in the early 2010s, researchers reported a significant breakthrough with CRISPR, the genome editing technique that has been likened to a “cut and paste” tool. While the Nobel Prize in 2020 was awarded to Jennifer Doudna and Emmanuelle Charpentier, other scientific groups advanced the work as well — including, importantly, the lab of George Church at Harvard. Using CRISPR allowed scientists to make dozens of simultaneous edits to pig DNA.
A company was spun out of Church’s lab called eGenesis to develop such pigs, and in 2017, their scientists reported the creation of the first pigs without PERV — a crucial step for xenotransplantation. My team at Leaps invested in eGenesis in 2019 to accelerate their vision of ending the global organ shortage.
In addition to CRISPR, advances took place in parallel in molecular biology, immunology, and next generation sequencing to allow for a better understanding of how to alter the porcine DNA to knock out certain genes and insert others to prevent rejection.
“eGenesis couldn’t exist ten years ago,” says their CEO Mike Curtis. “CRISPR-Cas 9 was only discovered eleven years ago, and that changed how we think about genome engineering. Our porcine donor has 69 edits. There was no way to do that before CRISPR.”
Other companies sprung up to try to commercialize xenotransplantation, including biotech company Revivicor, later acquired by United Therapeutics.
Revivicor supplied a porcine heart with 10 gene edits for the first transplant into a human patient, in January 2022, at the University of Maryland, on a compassionate use basis. The patient, who had end-stage heart failure, lived for two months. A second historic xenotransplant with an identical porcine heart from Revivicor happened in September 2023, but that patient died after six weeks.
Experts aren’t sure exactly why both patients succumbed when they did. Possible factors include their terminal underlying disease, the presence of a porcine cytomegalovirus, and the number or type of genetic edits engineered into the porcine donor.
Gearing Up for Clinical Trials
The big question today is whether the field is ready to progress to clinical trials with multiple patients, not just occasional one-off compassionate-use transplants in terminal patients.
“I do think we have sufficient data now to move this into clinical trials,” Dr. Montgomery says. “The pathway toward an IND seems to be getting clearer. It’s important that the FDA considers the loss of life that’s occurring because of the organ shortage.”
A landmark paper in Nature last year showed that monkeys who received a genetically engineered porcine kidney from eGenesis typically lived 176 days, and one even survived for more than two years.
A porcine liver with the same gene edits, also from eGenesis, recently demonstrated success for 72 hours serving as a liver support system outside the body in combination with a perfusion device. The system was tested on a brain-dead subject to determine if the porcine liver would continue to do the job of the liver for a short period. The experiment worked. Such a support system could be beneficial in certain types of patients with acute liver injury, such as from drug overdoses, to offload the functions of the liver while their own recovers, or to provide a bridge to transplant with a human liver.
“No matter whether it works in the long run, we will have situations where some kind of temporary liver support or bridge to recovery would be helpful,” says Dr. Brown, the Weill Cornell liver transplant physician.
Curtis says that eGenesis is now planning a clinical trial for the extracorporeal liver perfusion support system and hopes to begin it this year.
Dr. Montgomery predicts that the first clinical trials for xenotransplantation in the U.S. will start in 2025 with kidneys, since the organ’s function is less complex than a liver, and the stakes are not as high as a heart. If the porcine kidney fails, for instance, it can be removed, and a patient can go back on dialysis.
Curtis predicts that over 800,000 kidney patients in the U.S. alone could benefit if xenotransplants are successful. In addition to liver, eGenesis also has programs in development for kidney and pediatric heart xenotransplants. Their kidney program may enter clinical trials first in Japan, with a partner there. The unmet need for organs is even greater in Asia because they don’t recognize brain death consistently, which means a smaller pool of donors. Waiting lists there can be as long as 15 years.
In the U.S., the median wait for an organ ranges from several months to several years, depending on factors like age, blood type, and health status. There are more than 88,000 on the waiting list for a kidney, compared with nearly 10,000 patients waiting for a liver and about 3,300 waiting for a heart. About 17 people die each day waiting for an organ that never comes.
“After thirty years of development, the field is coming together,” Curtis says. “We’ve integrated all the findings into a single donor. We know enough about primates to move into patients for the first time, and I think regulators are in agreement. All the pieces are lined up.”
As an investor, doctor, and believer in the transformative power of biotech, I can’t wait to see what happens next.
Special thanks to Kira Peikoff for her additional research and reporting on this article.
The article was initially published on Forbes.com on February 7th, 2023
