• Dr. Ludger Wess

Carefree life with donor organs.

TolerogenixX 1Medical technology. People with donor organs must be on guard against infectious diseases throughout their lives. To prevent the organ from being rejected, their immune system must be suppressed. An infection could be a death sentence. Biotechnology companies are now working to preserve the capabilities of these patients' immune systems.

In Germany several thousand people receive donor organs - kidneys, livers, pancreases, lungs or hearts - every year. In Europe there are a few tens, worldwide several hundred thousand. They all have the same problem after transplantation.

"Every organ must fit immunologically so that it is not immediately rejected, i.e. destroyed, by the recipient's immune system," explains Matthias Schaier, co-founder and CEO of the Heidelberg-based biotechnology company TolerogenixX. However, despite all the doctors' efforts to find as many matching characteristics as possible in order to outwit the immune system, every donor organ remains a hostile intruder for the recipient's defence system. For this reason, the immune system of organ recipients must be suppressed for the rest of their lives by a drug cocktail. The consequence: the affected persons are particularly susceptible to infectious diseases and tumours.

Schaier, a specialist in autoimmune diseases, has been working on a solution to this problem for quite some time. Some years ago, together with his colleague Christian Morath, transplantation specialist at the University of Heidelberg and co-founder of the company, he finally developed an elegant method to prepare the immune system of an organ recipient for the donor organ in such a way that the rejection reaction does not occur. This did not limit the ability of the immune system to protect the body against infectious diseases and tumours. And the use of drugs with many side effects was also significantly reduced.

"Prior to transplantation, blood cells from the organ donor are taken and treated with our patented method," explains Schaier. "This can be done within one day. The organ recipient receives the treated cells and is ready for transplantation after one week.

"Treatment after transplantation is also conceivable," said Schaier, "for example, in patients with rejection. We have already tried to treat one patient with stem cell transplantation and published the results."

But this is only possible if you still have access to the donor's blood cells, that is, if the organ donor was a living donor and is still alive.

In order to bring the technology to market maturity, Schaier and Morath founded TolerogenixX in 2016. Morath explains the process: "The white blood cells of the organ donor are treated with mitomycin C, an antibiotic that is currently only used in cancer therapy. In the process, certain surface antigens are down-regulated, while genes that suppress the immune defence are activated".

The donor's treated cells are then administered to the recipient via an infusion. "Then they deactivate the cells that react to foreign surface antigens with an immune response," says Morath. This effectively creates an immune tolerance towards the donor organ.

TolerogenixX 2

This process lasts a few days and leads to the recipient's immune system no longer recognizing the implanted donor organ as foreign, but considering it to be the body's own tissue. This suppresses the rejection reaction, while the immune system's ability to recognise pathogens or tumours is maintained.

The procedure has now been tested in an initial clinical trial on ten patients who received a kidney as part of a living donation. The result: the procedure proved to be safe and well tolerated and no patients experienced rejection within the observation period - one year after transplantation. No antibodies against the transplant were found either. At the same time the transplants worked perfectly.

Transplant specialists Sam Kant and Daniel C. Brennan of the Johns Hopkins School of Medicine, Baltimore, called the results "encouraging" in a publication. If the results could be confirmed in larger studies, they concluded, "we will witness how the original goal of transplantation becomes a reality: that it goes from being a treatment to a real cure."

TolerogenixX is now preparing a larger patient study. "If everything works out, we will start this study at the end of 2020. If the results are positive again, we might be able to obtain a so-called conditional approval," said Schaier. This option was introduced in the EU in 2005 to make urgently needed new drugs with high benefits available to patients more quickly. These conditions usually include the requirement to complete phase III studies and carry out further investigations within certain time limits.

Schaier and Morath see further applications in the treatment of autoimmune diseases. The technology of TolerogenixX might also help to make the immune system tolerant to the autoantigens against which it acts in such diseases. Specifically, TolerogenixX is considering a study involving patients suffering from systemic lupus erythematosus, a chronic inflammatory autoimmune disease that damages the internal organs of those affected.

In the future, it may be possible to achieve what has long been impossible: to control the immune system without incapacitating it.

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Lucky?

In Germany alone, there were around 9000 people on the waiting list for a donor organ on 01.01.2020. In the EU, more than 150,000 people were waiting in 2018. The situation in the USA is not much better. More than a third of all people on the waiting list die each year without having received an organ.

Xenotransplantation, in which organs are transplanted from animals to humans, has therefore been a long-standing idea. If this succeeded, we could breed animals for organ removal.

Already today, people with non-functional heart valves often receive so-called "biological heart valves", which are made from aortic valves of pigs or from the pericardial tissue of cattle. However, transplanting entire organs is more difficult. Those of chimpanzees, our closest relatives in the animal kingdom, are too small and not powerful enough. Pig hearts are physiologically more suitable. They have sufficient pumping capacity, a suitable size, and the blood and metabolism of pigs have similar characteristics to those of humans.

However, two major obstacles stand in the way of using pig organs: firstly, the so-called hyperacute rejection reaction, which occurs minutes or a few hours after transplantation, and secondly, the risk of virus transmission.

The so-called retroviruses of pigs (PERV - porcine endogenous retrovirus) are particularly problematic. These are integrated into the animals' genome as a kind of "sleeper" and are therefore also passed on to the offspring. Under certain circumstances they can become active again and cause diseases.

The second problem is immune tolerance. In mammals, so-called surface antigens are found on the surface of all cells. These vary from species to species and within species from individual to individual. They help the immune system to recognize the body's own healthy cells. If the pattern does not correspond to the norm known to the immune system, the cell in question is eliminated by the immune system. Pigs possess surface antigens that do not occur at all in humans. While these can be removed chemically from heart valve tissue, this is not possible with organs. They provoke the hyperacute rejection reaction, which cannot be controlled even with drugs.

The US biotechnology company eGenesis is working on both problems. In 2013, the then 27-year-old Harvard student Luhan Yang co-authored a study that showed that mammalian genes can be removed or altered. Yang, who had already been a kind of bio-superstar in her Chinese home country as a high school student, had no problem convincing the world-famous bio-engineer Geogre Church that this would also solve the virus problem in pig organs. Together they founded eGenesis.

The project also fascinated investors, and so the company began operations in Cambridge in February 2015. The scientists were able to publish a sensation in November: They had succeeded in deactivating all PERVs in pig cells. However, this was initially only one cell line, informs Carmel. "We wanted."

Two years later, the company was able to breed an entire pig without endogenous retroviruses from a cell line treated in this way. Since then, there have been pigs in which all 62 copies of the 25 PERVs are inactive. The first one was named Laika, after the dog that in 1957 was the first living creature to be purposefully placed in orbit around the earth. eGenesis is now working on minimising the rejection reactions. To this end, human genes will be introduced into the pigs' genome to make the tissue of the organs more immune compatible and reduce the risk of blood clots forming.

If this work also works - although there is currently no time frame for this - there would no longer be a shortage of donor organs in the future.

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Author: Dr. Ludger Wess

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