Gene and cell therapy: impossible successes
"We have a prototype of an artificial chromosome"
Ru" said the Director of Science of the Institute of Human Stem Cells (ISCH) Roman Deev.
– At the conference, we are talking about two types of high-tech biotechnological methods in medicine: these are gene technologies and cellular technologies. Is it possible to compare them? Firstly, in terms of scientific development and, secondly, in terms of application prospects.
– In medicine, you can compare some areas if they are used to treat the same diseases. In general, there are diseases where both cellular technology and gene technology can be used, for example, chronic ischemia of the lower extremities. But each technique has pros and cons.
To work with cellular technologies, we need a legal framework, we need a certain infrastructure, we need formulated requirements for quality control. Medicines based on the gene therapy design fit into the existing legislation, into the existing standards of industrial practice.
Although it would seem that gene technology is a more subtle story, but it fits into the existing legal field, and with cells everything turns out to be much more complicated. Moreover, if everything is done qualitatively, in compliance with proper laboratory practice and proper production principles, it turns out that a cellular drug for the treatment of a particular disease will cost more than a gene drug. Although, in theory, a living cell inserted into a tissue produces a whole symphony of different factors, and a gene will produce only what is written in it – one, or at least two factors (if we are talking about two-cassette plasmid constructions).
But we must be realistic – gene technology can already be developed, implemented, tested, and helped by people, and with cells in our country so far it turns out to be an endless journey into the unknown.
On the other hand, there are points where these two approaches should definitely be used synergistically. There are groups of diseases in which it is impossible to achieve a therapeutic effect, unless you have carried out some genetic manipulations, having previously removed cells from the body. We, the researchers, modify the cells, then transplant them and count on a positive effect. This is called gene-cell therapy in our practice, and it is no longer possible to draw a watershed between both directions. If you refer to the website http://clinicaltrial.gov , then it turns out that several protocols of such clinical trials already exist. In particular, there is a protocol where gene modification of hematopoietic stem cells occurs, in which the gene responsible for the synthesis of one of the surface molecules to which HIV clings is damaged. As a result, the membrane of these cells becomes impervious to the virus.
A modified bone marrow is transplanted to the patient, which gradually replaces his own cells, and thus the virus loses its "food base". But this method is being investigated for patients who have indications for bone marrow transplantation, that is, for those who develop malignant bone marrow diseases against the background of HIV.
And the muscle theme (gene therapy of monogenic neuromuscular diseases), which was repeatedly voiced today at our symposium "Topical issues of gene and cellular technologies", is an even more complicated story. The fact is that the muscle consists of hundreds of thousands of fibers, which are the result of the fusion of a large number of cells, with their own special surface structures, with a contractile apparatus inside, designed to constantly perform a very specific function. In this complex machine, you need to put some kind of cell, some kind of gene, and in this fiber there may be several dozen nuclei, each of which produces information about protein synthesis. How to take all this huge fabric economy and reboot? This is a huge problem. You can make a gene construct, you can make an artificial chromosome, but how can it be delivered efficiently so that it works? So far we don't know how to do what cells can do.
– You started your report with the fact that gene therapy is far from fantastic, and yet only five gene therapy drugs have been registered in the world against the background of more than two thousand clinical trial protocols. And what is the reason?
– There is a principle of "do no harm". The state bodies regulating the process of clinical trials are largely guided by this principle. And in some cases – only by this principle, and they believe that it is better to prohibit than to allow.
As a result, a clinical trial can last for decades. For example, Finnish colleagues (Petar Korpisalo, Ark Therapeutics), who today reported on the treatment of lower limb ischemia and their gene constructs with viruses, have been conducting clinical research for 20 years, constantly changing their gene constructs. But if development was the edge of science 20 years ago, today, after it has passed all the stages of the purgatory of registration actions, modern technologies are breathing down its neck. 20 years is a lot for biotechnologies.
That is, today the regulatory system slows down the process. But this is braking with a plus sign, because in such a situation, "it's better to overdo it than not to do it." Otherwise, then you can have unpleasant consequences.
On the other hand, there is a certain period of romanticism in any topic. 20 years ago, scientists thought: we have made a gene construct, now we will launch this program into the cell, and it will obediently begin to synthesize something there. Many protocols were registered on this wave, and it turned out that a living organism, as a nonlinear, multifactorial system, can gradually withdraw them all. This led to the realization that in most cases the proposed gene constructs are imperfect. This is not because scientists are bad, but because we simply have not yet reached that fine level of understanding of intracellular processes to make such a wonderful working design that would be effective in all cases. In addition, in a living organism, both physiological and pathological processes are always repeatedly duplicated. It seems to us that we are acting on some link with our gene medicine, but nothing happens. It turns out that there are still twenty duplicate contours that negate all our efforts. Therefore, subjectively, of course, it seems to us that 20 years is a lot, but for the history of science as a whole it is not a very long time. The main applied discoveries are still ahead.
– You said that you have been waiting for about a year for permission to conduct clinical trials of a gene-activated bone graft. And as for clinical trials of cellular drugs, is this even more difficult?
– Yes, it's a sad story, with our development – the cellular drug "Gemacel", we have been breaking through this wall for about four years. Moreover, we change protocols according to the requirements of officials, get the approval of the ethics committee, undergo various examinations, have positive conclusions on hand. And nothing.
– Does the absence of a law on cellular technologies interfere? Or will it be even worse with him?
– We conducted a survey on this topic in our journal ("Cell Transplantology and Tissue Engineering"), when there was another attack of legislative activity in our professional community (September 11, 2011). So, more than half voted for the point: adopt at least some law, it is impossible to work! We are standing still, marking time. Let me take a step forward.
It's like banning car traffic on the basis that we have some kind of wrong traffic rules. "And we will change them, but for now we will ban driving altogether," the official would say. Therefore, the number of clinical trials of cellular technologies has fallen to a critical level, that is, almost to zero. At the same time, I don't want to discuss underground things, we work in the legal field.
– But against this background, you managed to conduct clinical trials very quickly and register "Neovasculgen". How did you get so lucky?
– No, it's not "lucky", it was a titanic work. And we didn't start from scratch, we stood on the shoulders of our predecessors. The principle of creating plasmid structures has been known for twenty to thirty years. How to make it is a clear technology. All problems begin at the stage of registration actions. The gene design needs to be checked – it seems to work on animals, but, as a rule, when a person appears in this case, everything starts to work not as well as in the experiment. The strong-willed qualities and the organizational and legal form of researchers play a very important role here. We came to Finland and asked: why have you been conducting clinical research for 20 years? And you need to understand that this is a university team (Ark Therapeutics) and it has a different principle of existence – to receive grants, to do research, to publish. We have a different task – we are a commercial organization, our task is to make, check, in case of safety and effectiveness, register and implement in practical healthcare, produce and sell. We have a different paradigm of existence. Therefore, it was necessary to gather the will into a fist, invest, make a start and come to the finish line in a few years.
And if you count how many years have passed… If I'm not mistaken, the patent was filed around 2005, received in 2007. This means that the work had to be started at least two years in advance – in 2003, or even in 2002. Then the pre-clinic, clinic, and we registered the drug only in 2011. If you count everything, you get eight years. And with the establishment of the production process – all nine-ten.
–But not twenty.
– Not twenty, because we could take the developments of our predecessors in open publications that existed before us. These developments were also in our country. Including the development of the drug "Corvian", in which a plasmid gene design is also used as an active principle. And at the time we started clinical trials, they were already in the second phase. I was still at the Scientific Center of Cardiovascular Surgery named after him. Bakuleva prototype of the drug "Angiostimulin".
– What is the cost of your drug and the cost of treatment?
– This question should be asked to the commercial director. The drug is on the market and its price is on reference pharmacy websites.
– But still, how expensive is it and can this treatment ever become available?
– We do not sell the drug, we conclude an agreement with professional pharmaceutical sellers for this. This company naturally adds something to the cost. Therefore, when the drug enters the market, its cost is somewhat different from the one we are positioning. It seems, at first glance, that the amount is large. But if you look into it, patients with lower limb ischemia receive some kind of treatment. Let's say they are shown treatment with prostaglandin group drugs. The effect of our drug lasts two to three years.
"And after that?"
– The trend is going down, but still does not reach the level of the beginning of treatment. Although today there are observations of the effect for up to four years. But in two years, the patient should receive four courses of prostaglandins, and each course (if it is of high quality) can cost from 40 to 60 thousand rubles. If you add it up, you get the same amount.
– And yet, how exclusive is gene therapy today?
– In order for it not to be exclusive, the state should turn its head towards its citizens. Indeed, the drug turns out to be expensive, and not every citizen of Russia or Ukraine, where he is also registered, can afford it. But there is a clear pharmacoeconomical justification here. Either a person loses a leg in two years, becomes disabled, and the state spends money on him, or a person can be treated. We have various government programs. But in order to get into them, the drug must live a certain life. It should exist on the market for some time, independent expert opinions should appear on it, there should be certain requirements for production. And we are still at the beginning of the journey, very small.
Of course, we are not just waiting for the state to turn its face to us, we are working. Now our team responsible for Neovasculgen spends 70% of its working time trying to turn the state towards these patients. In the country, and in the world, the problem of lower limb ischemia is gaining momentum. For example, I talked to surgeons from Buryatia, and they say: there has never been such a thing that the Buryats, people of the Eastern type, had such pronounced atherosclerosis. And now they are indistinguishable from the European population in terms of morbidity. Recent data from global meta-analyses on the epidemiology of atherosclerosis of the vessels of the lower extremities not only do not refute, but emphasize this trend (Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. August 1, 2013. The Lancet. The global pandemic of peripheral artery disease. August 1, 2013. The Lancet).
– If we return to the scientific side of the question, are specialists now moving from viral gene delivery to plasmid delivery? Is a plasmid better than a virus?
– You can't say that. With any disease, we have to weigh what is better, what is worse. Here's a look at how the choice of a technology platform for a specific task can take place. For example, we are developing a gene construct for the treatment of chronic lower limb ischemia. We have a construct with the gene of endothelial vascular growth factor, which triggers the growth of blood vessels. We want it to work constantly and the factor is constantly being developed with a high risk of developing something bad, since the vessels will constantly grow somewhere? Or do we just want to spur the process? In this case, we prefer temporary expression rather than permanent. So, we can already sweep away a whole category of viral constructs that integrate into the genome. There remain adenoviruses (they do not integrate) and plasmids. Again, it is necessary to evaluate the side effects: adenoviruses are a flu–like syndrome, sorry, "snot to the knee", fever. In addition, immunization occurs, which can reduce the effectiveness. However, adenovirus and plasmid designs are not the same in terms of penetration efficiency: adenovirus penetrates an order of magnitude better. But the complications that arise are undesirable, and the effect is ultimately comparable.
– Tell us about the artificial chromosome. You are also engaged in this direction, aren't you?
– This is an absolute investment in the development of science for us. This is deeply fundamental research, and it will be fundamental research for another ten years before it will be possible to talk about something else. But this is scientific high-tech, it's interesting. There are partners abroad who have made progress in this, but not too far – if we try, we can catch up with them in a couple of years.
– And what is an artificial chromosome?
– This is a chromosome in which there is nothing, except for the sequences responsible for doubling itself (DNA), and the very therapeutic gene that interests us. That is, the telomere, centromere and therapeutic gene. The assembly technology is the first stage. And then we need to put it inside the cell we are interested in so that it works. It is necessary to make sure that the cell is deceived and starts working with more chromosomes than it should. Today we are at the equator of solving the first problem: my colleagues and I (A.N. Tomilin) have a prototype of an artificial chromosome. But the next problem is the method of its effective delivery to the tissues. And I can't even predict how many years this research story will take. We are interested in this as scientists, and this is an element of our company's social responsibility – we can not only earn money, but also effectively invest in the future health of the nation.
Portal "Eternal youth" http://vechnayamolodost.ru11.11.2013