Between Scylla and Charybdis

Scientists will determine the optimal requirements for cellular preparations

Natalia Bulgakova, "Search"

Faculty of Fundamental Medicine (FFM) Lomonosov Moscow State University is one of the leaders in the field of development of gene and cell therapy and research of tissue regeneration mechanisms. The faculty's scientists have already completed more than a dozen government contracts for the development and preclinical testing of cellular drugs. However, the project that the faculty's scientists are currently carrying out within the framework of the Federal Target Program "Research and Development in priority areas of development of the Scientific and Technological complex of Russia for 2014-2020" (Federal Target Program IR) is special. Firstly, in addition to MSU (the recipient of the subsidy and the coordinator), seven other leading state medical, research and expert organizations participate in it. Secondly, the topic of this project was included in the Federal Target Program by order of the Government of the Russian Federation. And thirdly, one of the results of the project will be a very important and long-awaited document of national importance – the National Guidelines for Preclinical Testing of Biomedical Cell Products.

Gene and cell therapy, or regenerative medicine, is a very young and rapidly becoming popular direction. The first studies began in the late 90s of the last century. And already in the two thousandth years, even in serious newspapers, you could see fantastic ads: businessmen from medicine offered treatment with stem cell drugs, promising patients rejuvenation and getting rid of almost all diseases – from schizophrenia to lameness. The advertising, of course, was silent about the fact that the technologies are so new that the long-term effects of their use are still unknown, and cellular drugs have not actually been recognized by the state yet.

The Federal Law on Cellular Technologies, the draft of which has been actively discussed by the community for ten years, is intended to introduce the production of cellular drugs into the legal field, legalize the algorithm of their creation and preclinical testing, as well as the licensing procedure. But experts have reason to hope that this Federal Law is about to be adopted and will come into force in the next year or two. This is where the National Leadership will be needed, which will prescribe specific requirements.

The head of the Federal Target Program IR project "Development of a technological platform and methodological recommendations for conducting preclinical studies of biomedical cell products", Dean of the Lomonosov Moscow State University FFM, Academician Vsevolod TKACHUK tells:

– Regenerative medicine is a fundamentally new medicine, officially it does not seem to exist yet. We are talking about growing dead or missing cells of the body. A person is constantly being updated throughout his life – every day old cells die and new ones arise. We produce three tons of blood cells alone in our lifetime, and if we count other tissues, we will get more than a dozen tons. Scientists already know the mechanism of cell death and renewal, but it was unclear how it could be affected. If, for example, as a result of a heart attack or Parkinson's disease, the cells died, how to make them become alive again? Traditional medicines will not help here. It is necessary either for the necessary cells to be formed in the body itself, or to grow them and somehow "plant" them into the human body.

Regenerative technology involves the use of not only stem cells, from which any other cells can be formed, but also "reprogrammed" ones. Since all cells originated from one, embryonic, their genetic apparatus is the same. During the formation of an organism, cells differentiate – some turn into muscle cells, others into nerve cells, and so on. Now scientists have learned how to get cells of another type from one type of cells. When injected into the body, they will not be rejected by them, since they are obtained from "native" cells.

Such technologies open up tempting prospects for humanity, but it is necessary to act very carefully here. After all, it is very dangerous, in fact, that cells of one type can turn into any other. You need to be able to regulate this process, be able to run a program to transform into the right type of cells. It is necessary to understand how this transformation takes place. And finally, it is necessary to ensure that the cell does not turn into a tumor. After all, we break her program. Oncology is basically a genetic failure of cells, and here we make this failure consciously and must be sure that we will not make it worse. Of course, we cannot predict what will happen to a person 20 years after such treatment now – we need him to live these years. Therefore, for the time being, cellular technologies should, in theory, be used in dangerous, terminal cases, when a person will die without such treatment. Nevertheless, they are used even in cosmetology. It should be understood that the desire to get rid of wrinkles can lead to a great tragedy. This became possible due to the fact that there is no regulatory law. But there are people who consider what is not forbidden to be allowed. In this case, the thesis is inhumane, from my point of view.

There are many examples of the development of cellular technologies in Russia. At our faculty, for example, they learned how to grow vessels and nerves from cells. Then we plant them in animals whose immunity is suppressed in a special way (so that their body does not reject human cells). At the N.I.Pirogov RNIMU, scientists are developing a technology for producing artificial skin – it will allow saving people whose burn has exceeded 50-60% of the body surface. These patients without skin grafts would be doomed, and thanks to cellular technologies, even with burns 80-90% chance of survival remains. Our industrial partner in this project, Seller Farm LLC, is engaged in the development of personalized drugs for the restoration of cartilage tissue defects through autologous chondrocyte transplantation and participates in the introduction of drugs for immunotherapy for oncological diseases. In the North-Western Federal Medical Research Center named after V.A.Almazov, bone marrow stem cells are used for the regeneration of blood cells, in the Russian Cardiological Research and Production Complex, heart stem cells are grown, in the Moscow Research Oncological Institute named after P.A.Herzen, in order not to amputate a limb due to a tumor, a piece of bone is grown outside the body and then they are planted, replacing the bone defect. All these organizations are co–executors of our project.

– And what is its essence? What should you pay attention to when setting rules for the use of a particular technology?

– In medicine, all procedures, diagnostic methods, drugs are regulated by the Ministry of Health. As for medicines, before giving them to people, you need to check their effect on animals. These are so-called preclinical trials, they take from three to five years. It is necessary to prove that the drug is, firstly, effective and, secondly, safe. Then it takes about ten years for clinical trials: doses, treatment regimen are selected, effects, direct and side effects are studied. If the medicine is effective, it will be used. But all the same, only after 20 years it will become known whether it prolongs life or vice versa... If it shortens by four years or more, they refuse it, in other cases they leave it.

According to the existing rules, the same procedure should be followed for cellular preparations. But there is no law for them yet. The draft Federal Law on cellular technologies was adopted in the first reading, the second and third should take place before the end of the year. We hope that this Federal Law will come into force in 2017. And then the question immediately arises: how to conduct preclinical trials of cellular drugs? You will need a manual that would prescribe how to get the right cells so that they are safe and effective; how to test their effect on animals; how to prepare these animals so that their body does not reject human cells or tissues grown from these cells; how to keep animals, what requirements for vivariums and laboratories to provide, and the main thing is where to inject these cells, how to inject them, how to monitor whether they are alive or not and what they turn into; how to find out that the genome of cells has not been rebuilt in the process of work, that some genes and chromosomes have not been lost. The most complex set of questions!

All project participants have their own experience in this field. We are also studying world practice. Of course, there are similar developments in the USA, the EU, and other countries. But it would be wrong to copy them: we don't have much of what is there. We need to proceed from the Russian capabilities – methodological, financial, intellectual. Not to lower the bar – so that cellular drugs do not become dangerous to humans, but also not to overestimate it so that the development of these technologies will slow down for twenty years. People are dying…

– It's just like walking between Scylla and Charybdis…

- yes! Therefore, not only scientists, but also active doctors and experts of the Ministry should participate in the creation of such a provision. There is an Expert Council on Regenerative Medicine under the Ministry of Health, I head it, dozens of specialists from all over the country are gathered in it. There is also the National Society of Regenerative Medicine – this is already a purely public organization that unites doctors and scientists, several hundred people. We, the executors of the project, interact with the public organization, the Ministry of Health, and the Expert Council, involve them in discussing controversial issues.

...Pavel MAKAREVICH, head of the regenerative medicine laboratory, graduate of the MSU FFM, now a senior researcher at the Faculty, Candidate of Medical Sciences, "one of the best specialists in the country on regenerative medicine and a key figure in the project from MSU," as presented by Vsevolod Tkachuk, shared his opinion about this project.

– Now the fourth stage of the project is underway, the penultimate and in general the key one: the final synthesis of the accumulated experience has begun, - Pavel Makarevich said. – I want to emphasize that the project itself is very reasonably arranged: not only scientific, medical, educational organizations participate in it. The co-executors also include the Center for the Examination of Medical Products: it helps us with issues that relate to legal aspects. Our industrial partner also actively provides us with comprehensive advisory support: their strong point is their production experience. This company has a full-fledged technological base for the production of drugs of this class in Russia. It needs a legal framework, a federal law, within which it could become a serious player in the market and receive its dividends from this. Therefore, it is very interested in this project and in interacting with scientists.

– Does the industrial partner invest financially in this project?

– No, initially the extra-budgetary funding was zero. In order not to give the impression that we are writing a manual that is convenient for her by order of a certain company. This work should be independent and transparent.

– And what is the situation with the production of cellular drugs in Russia today? Something is being produced, isn't it?

– Constantly, serially, on an industrial scale – no. The fact is that the lifetime of a cellular drug is several days, after which its properties are sharply lost and it becomes ineffective. Things are like this in the world: there are large university clinics with their own production sites. Clinics have a license to manufacture, and they produce cellular drugs in small batches – for testing and for patients in need, according to the needs of specific departments or institutions. So it's not worth expecting that we will immediately start producing these drugs in huge batches in Russia, like antibiotics or anti-arrhythmia drugs. In our country, serious research in this area was conducted with the permission of the Scientific Councils of institutions, cellular drugs were produced, but in accordance with existing norms, these were unique one-time actions to save the lives of patients who needed it. In the new conditions, after the adoption of the Federal Law, it will be possible to create a full–fledged industry in Russia, when testing, production and application are conducted according to a single regulation.

Portal "Eternal youth" http://vechnayamolodost.ru  21.03.2016