25 September 2017

Pigs will come to the rescue

Maxim Rousseau, Polit.roo

For a long time, xenotransplantation, that is, the transplantation of human donor organs from other animal species, was considered impracticable. Due to immune rejection, donor organs simply could not take root in the body. But in recent years, the situation has begun to change. At the 14th Congress of the International Xenotransplantation Association, which just ended in Baltimore, the researchers were optimistic. The most likely candidates for donors for human patients are called monkeys and pigs. It is worth mentioning that immediately after the closing of the congress, many of its participants continued their work at the 6th International conference "Pigs in Biomedical Research", which will end on Monday. The materials of the congress are published in a special issue of the journal Xenotransplantation.

Learning to overcome incompatibility and use donated animal organs is a really important task. Xenografts can save thousands of lives. After all, until now, from 20% to 30% of patients who need an organ transplant die without waiting for a potential donor. But to do this, it is necessary to deceive the patient's immune system and make it perceive the animal's organ as its own.

Genetically, chimpanzees are the closest to humans. In addition, their organs are similar in size to human ones. But chimpanzees are too few, so baboons are another candidate. There are quite a lot of them, but a number of problems are associated with them: baboons' organs are smaller than human ones, they rarely have a zero blood type, and pregnancy lasts for quite a long time – which means that after preparing an embryo with the right properties, doctors and the patient will have to wait a long time for its birth. In addition, the proximity of monkeys to humans not only facilitates possible xenotransplantation, but also poses a threat: their diseases are also close, so there is a high risk of transferring them together with a donor organ.

Therefore, domestic pigs are most often considered as possible candidates for donors. Their more distant relationship with humans reduces the risk of disease transmission. Pig organs fit us in size. And pigs are definitely available in large numbers. In modern xenotransplantation experiments, pigs most often act as a donor, and baboons as a model of the human body.

In 2014, researchers from the National Heart, Lung, and Blood Institute (NHLBI) they managed to ensure that the hearts of genetically modified piglets implanted in the abdominal cavity of a baboon remained alive for more than a year. They genetically modified pigs that donate organs, removing from their genome a number of genes that cause an immune response in humans, and, conversely, introducing some human genes there. They also developed methods of specific immunosuppression, which prevents rejection of the donor organ, but does not suppress the immune system of the body as a whole.

The transplanted hearts were placed in the abdominal cavity of baboons and connected to their circulatory system. The researchers found that in one group, the average life span of a transplant was more than 200 days, sharply exceeding the terms in other groups (from 21 to 80 days). Three donor hearts continued to beat for 200 to 500 days and were alive at the time of submitting the article to the journal.

The pigs whose hearts were used in this experimental group had a human gene encoding the protein thrombomodulin in their genome. Human thrombomodulin made it possible to avoid blood clotting in the capillaries, which was previously a characteristic phenomenon during transplantation. Another factor that ensured success was the use of hybrid antibodies obtained from mice and rhesus monkeys (2C10R4). In the group with the longest survival, no complications were noted, including infections

Another possible method involves the use of human induced pluripotent stem cells (iPS cells), which are injected into pig embryos. Earlier this year, a similar experiment was conducted by a group from the Salk Institute for Biological Research in San Diego. The modified embryos were implanted into female pigs and their development was monitored for a month. Although scientists transplanted about two thousand embryos, only 186 of them survived in a month, and even then some developed more slowly than normal. However, the surviving human cells inside them were found. In the near future, this method allows testing drugs on human tissues in the pig's body. And in the future, perhaps, it will allow pigs to be raised with human organs prepared for transplantation.

A heart transplant specialist from the University of Maryland Medical School, Mohammad M. Mohiuddin, under whose leadership the 2014 experiment described above was conducted, said at the current congress: "What we thought was very far away seems to be becoming the near future." He moderated one of the sections of the congress at which scientists discussed the possible use of xenotransplantation with representatives of the US Federal Agency for Food and Drug Administration (FDA), whose permission must be obtained when introducing any new drug or treatment method in the country.

Scientists found something to demonstrate to their colleagues and FDA employees. Parsia Vagefi from Harvard Medical School spoke about the new experience of liver transplantation from pigs to baboons. If before that the record of survival after such a transplant was equal to nine days, now two baboons have lived after it for almost a month. Earlier this year, a team from Emory University announced that the kidney of a genetically modified pig was able to live for more than 400 days in the body of a rhesus monkey, breaking the previous record by more than 250 days. And directly at the congress, a group of researchers led by Bruno Reichart from the University of Munich reported on a new successful experience in transplanting a pig's heart in a baboon's body.

The experiment of Reichart and his colleagues was designed for 90 days, but even after reaching this period, the experimental baboon was, as the scientists said, "in very good condition."

This is the first time a baboon with a transplanted heart has reached the milestone of three months of life after surgery. Even 20 years ago, the International Xenotransplantation Association defined such a period as necessary for experiments on animal organ transplantation to be carried out on humans. However, another condition must be fulfilled: 60% of the animals that received the transplanted organ must live for at least three months. Now the staff of the University of Munich intend to continue experiments with baboons. They hope to move on to clinical trials of pig–grown heart transplants in two to three years.

But there are still a lot of unresolved problems. Researchers are not yet able to give patients a donor pig organ that will work in their body for the rest of their lives. It is not possible to achieve serious success in xenotransplantation of lungs. The donor's immunity in the case of a lung transplant has to be weakened so much that the experimental animals survive only a few days. Martina Rotblatt (United Therapeutics Corporation), CEO of United Therapeutics Corporation, which owns Revivicor, the main supplier of genetically modified pigs, says that xenotransplantation can become a "commercial hit" only in the case of successful organ transplants to tens and hundreds of thousands of people, and such a number is unlikely to be achieved with poorly adapted organs that will require a huge amount of immunosuppressants.

But scientists believe that even without achieving an ideal xenotransplantation, they will be able to offer their methods for clinical practice. As David Cooper from the University of Alabama, who is busy with problems of immunity during transplantation, explains, patients who need a kidney transplant should undergo a weekly blood dialysis procedure. Their life would be greatly facilitated even by a temporary kidney from the pig's body, which will not work for a long time due to gradual rejection, but will allow them to wait for a suitable kidney from a human donor.

Portal "Eternal youth" http://vechnayamolodost.ru  25.09.2017

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