Will human beings one day be able to live with pig organs? The hypothesis was still science fiction a few years ago. But rapid advances in xenotransplantation – transplants of animal organs into human beings – could be a game-changer. Something to give hope to the many patients who suffer from organ shortage, a major public health problem that affects all countries in the world. In France alone, out of 27,802 transplant candidates in 2021 – including 10,983 on the priority waiting list – only 5,276 were able to receive a transplant, according to figures from the Biomedicine Agency.
This hope is further reinforced by recent work by French researchers. On August 18, the team of Pr. Alexandre Loupy, nephrologist and director of the Paris Transplantation Institute (Pitor), from Inserm, Paris Cité University and AP-HP, published , in collaboration with the Langone Health Institute (New York, USA), a study in the journal The Lancet. These scientists explain that they have elucidated the mechanisms involved in the rejection occurring after a transplant of genetically modified pig kidneys in humans. A great medical and scientific first. They also identified therapeutic solutions to prevent rejection of porcine organs, as well as genetic modifications to be made to porcine models to improve organ tolerance. “These discoveries confirm the progress made over the past ten years in this field where everything is accelerating, to the point that xenotransplantation has become a major subject in the world of organ transplants, opening up a field of possibilities to one day solve the shortage of organs in the world”, enthuses Pr. Alexandre Loupy, co-author of the study.
A giant leap in the space of five years
To fully understand the extent of their discovery, it is necessary to go back in time. The first experiments, with monkeys, began several decades ago. But the track was ruled out for ethical questions and because of the excessively high costs of breeding. The pigs then imposed themselves as the best candidates. Not only do we raise a large number of them in order to eat them – which limits ethical questions – but their price is lower, since their growth is rapid and their litters are numerous. They are, moreover, physiologically and morphologically close to us. Our organs, immune systems, metabolisms and our diets are similar.
Nevertheless, the porcine xenograft quickly encountered limits. The first came from the fear of transmission of porcine viruses to humans. The problem was partly solved thanks to a Sino-American team which explains, in a study published in the journal Science in 2017, having succeeded in genetically modifying pigs – using the Crispr-CAS9 gene editing technique – so that they no longer express porcine retroviruses. The technology was then patented by the company eGenesis. In parallel, another company, Revivicor, has developed a technique of raising pigs in drastically controlled environments so that they are “germ-free”. Since then, the first xenografts from pigs to humans have been authorized in the United States, in particular on brain-dead patients. The first promising results have partly dismissed fears related to potential virus transmissions.
The second limit, more complex, came from the “acute rejection” of pig grafts because of the interspecies immunological barrier. “Swine xenografts have long been considered science fiction because the immune system and antibodies of the human recipient perceive the graft as a foreign body, attack it and destroy it in just a few minutes”, explains Dr. Valentin Goutaudier , nephrologist, researcher at Pitor and main author – with Dr. Alessia Giarraputo, also researcher at Pitor -, of the study published in The Lancet. A phenomenon linked in particular to the fact that, unlike higher primates – including humans -, pigs express, on the membrane of their organ, a sugar (alpha-1,3-gal) against which the human body directs its antibodies.
But once again, gene editing has come to the rescue of scientists. From 2004, American teams announce to have genetically modified pigs in order to inactivate the genes which express this sugar. In 2018, german scientists manage to transplant a genetically modified pig’s heart into primates, which survive more than a year without rejecting the pig’s organ. At the same time, several American teams are grafting successfully, again in primates, genetically modified pig kidneys. “These discoveries constituted a revolution, underlines Valentin Goutaudier. From that moment, xenotransplantation was no longer science fiction at all”
“Invisible” reject traces with standard technology
And indeed, on the basis of these promising results, a team from the School of Medicine at the University of Maryland (United States) is performing, in 2022, the first transplant of a genetically modified porcine heart into a living patient. , but whose condition was so serious that he was not eligible for a conventional heart transplant, or even an artificial heart pump system. This “compassionate transplant” allowed him to survive two more months, before the heart was finally rejected.
Their feat followed one announced in September 2021 by researchers at the Langone Health Institute. The latter had succeeded, for the first time, in transplanting a genetically modified porcine kidney into a brain-dead patient, without observing the slightest rejection. “When we learned of this, we offered to analyze samples to confirm that the kidney had been accepted by the donor, says Prof. Alexandre Loupy. We suspected an undetected rejection.”
Indeed, unlike their American counterparts, the French researchers discovered traces of rejection “almost invisible with standard microscopy technologies”. A discovery made possible thanks to cutting-edge technology – a molecular biology platform – which allowed them to “carry out a fine analysis of the tissues”, specifies Alexandre Loupy. His team then pushes the investigations to understand the mechanisms of this rejection in order to be able to propose an optimization of the models of genetically modified pigs, even an improvement of the anti-rejection treatments. “Our technology has not only made it possible to highlight this rejection, but also to find the genes involved and to know where they are expressed in order to locate the cells which overexpress these genes”, specifies Valentin Goutaudier. These are the results that the French researchers describe in their study published in The Lancet.
Towards the end of pig organ rejection?
In this work, they explain having discovered a hybrid immune response similar to that observed during human organ transplants. According to them, the cells involved in attacking the genetically modified pig kidney are the same as those attacking human grafts. “Our analyzes revealed that the rejection-related antibodies were not directed against the sugar alpha-1,3-gal, but towards other proteins present in pigs and for which no genetic modification has yet been made. made,” says Dr. Alessia Giarraputo. Enough to allow Prof. Loupy’s team to propose, in their study, new genetic modifications of pigs in order to limit this mechanism of rejection.
As soon as they learned of the French results, American researchers from the Langone Health Institute immediately adapted their genetically modified pig models. And on July 14, they performed a transplant, on a brain-dead patient, of a new pig kidney that had undergone ten genetic modifications. According to an Aug. 16 statement from the Langone Health Institute, the kidney continued to function 32 days after it was transplanted. A record. “It’s even better than what we expected, rejoices Valentin Goutaudier. Now, everything can go very quickly and we will soon be able to consider transplants on living patients!”.
Motivated by the results of these different teams, the National Institutes of Health (the Institutes of Health in the United States) authorized a new wave of clinical trials in order to further push xenotransplantation experiments. They also selected the French team to lead the analyzes of future xenografts. Excellent news for French research, which remains behind in this field compared to the United States, China or even Germany. Excellent news, too, for patients awaiting organ transplants, since if science continues to progress at the same speed, porcine xenografts could represent a real alternative in just a few years.