Fast vascular growth factor. Growth factors

Injection will grow new veins instead of old ones

The Human Stem Cell Institute has presented a drug that promotes the growth of new blood vessels instead of deformed ones.

A Russian biotechnology company was the first in the world to launch mass production of a drug that grows new blood vessels to replace old ones clogged with cholesterol plaques. The medicine is called "Neovasculgen", its injections cause the capillary network to grow chaotically. The developers say that this method of treating ischemia is the only alternative to surgery in advanced cases of the disease.

We made a pilot batch of Neovasculgen. Now it is undergoing state certification, and after that the drug will go on sale. All phases of clinical trials have been completed, Roszdravnadzor has approved it, and the Ministry of Health has issued a registration certificate. I expect that within a month the drug will begin to be supplied to hospitals under various programs,” HSCI General Director Artur Isaev told Izvestia. The principle of action of the drug is to use a special gene VEGF 165, which forces the body to grow new blood vessels. Most of the drug that enters the body is destroyed almost immediately - it is processed by the liver and spleen. But about 1% of the gene is absorbed by cells in the area of ​​its introduction, and this gene forms a protein in the cytoplasm that is responsible for the creation of new blood vessels. The protein is released from the cells into the intercellular environment - into the muscle tissue; the nearby vascular cells begin to divide: new capillary tissue grows, gaps form in it, layers form, and ultimately a network of vessels is formed. The process fades and stops after natural cleaning occurs in the cytoplasmic cell - the substance is removed from the body. The patient is given a second injection, and the process continues until a biological shunt is formed - a network of blood vessels that connects the bloodstream on either side of the narrowing. This creates an alternative pathway and restores blood flow.

HSCI says that the medicine helped 94% of the subjects: their pain-free walking distance increased several times (a key indicator for coronary artery disease). Five out of 140 subjects failed to avoid limb amputation. But it was possible to delay it: radiographs showed an increase in the capillary network in all subjects.

According to the creators of the drug, registration of the drug in Ukraine has begun, then they hope to enter the European market by agreeing to sell the drug to a partner.

Investments in a new means of combating ischemia, according to Artur Isaev, amounted to several million dollars, and the funds of investors, mainly top managers of HSCI, and the profits of a subsidiary, Gemabank, a bank for storing umbilical cord blood stem cells, were used. "Neovasculgen" will be produced on the basis of the Hematological Research Center (FSBI GSC) of the Ministry of Health of the Russian Federation. HSCI plans to distribute 1 thousand packages by the end of the year, then production will increase and increase to 40 thousand packages per year. One package of the drug will cost the distributor 80 thousand rubles, a course of treatment will cost 160 thousand rubles. Note that alternative treatment options for ischemia are also not cheap: a standard operation for vascular prosthetics, according to Isaev, costs about 300 thousand rubles.

The director of the institute has no doubt that the medical product will be commercially successful due to the bleak situation with coronary disease in the country. According to HSCI, at least 1.5 million Russians suffer from a narrowing of the lumen of blood vessels and a decrease in their patency. At the same time, 144 thousand people are diagnosed with a severe form of the disease every year, and 30–40 thousand patients have their limbs amputated every year. Theoretically, all these people could be helped by Neovasculgen.

The Ministry of Health confirms that the drug is effective and has promise for the treatment of atherosclerosis or thrombosis.

Of course, Neovasculgen will be indicated for those conditions in which the blood supply to tissues is disrupted. But this is a wide group of patients, and one drug is clearly not enough to treat them. To treat ischemia, a complex of drugs is needed, just as for hypertension, for example, clonidine alone is not enough. The Bakulev Cardiocenter has a similar drug, Corvian, which is undergoing the third phase of testing. Similar tools are being developed abroad. And if they have not passed clinical trials, that means there are still questions about their effectiveness,” says Izvestia’s source at the Ministry of Health.

Experts note that in different countries of the world they are now trying to invent about 20 drugs that use the same principle to solve the same problems as the HSCI drug.

In our country, no one except HSCI has made any progress in this direction. But this is a risky startup for the institute, taking into account the funds they invest in it, says David Melik-Huseinov, director of the analytical company Cegedim Strategic Data, pharmaceutical expert. - How the drug will behave in practice is still unknown - there are questions related to medical evidence and the pharmacoeconomics of this drug. In addition, there are other conservative ways to treat ischemia.

Doctors expect a breakthrough in the treatment of cardiovascular diseases using genetic engineering - the discovery of fundamentally new drugs. The Ministry of Health says that the most promising developments are related to the enzyme urokinase (used to treat thrombosis), which has also been found to have properties that stimulate the growth of blood vessels. The drug based on this protein, Yupikor, has already passed the preclinical testing phase, with testing on humans ahead.

Konstantin Pukemov

Already in July, the first Russian gene therapy drug for the treatment of vascular ischemia in the legs may appear on the market. Last September, neovasculgen (as it is called) was registered with Roszdravnadzor. It is possible that it will soon be offered for government procurement. The biotech company that created the drug, the Human Stem Cell Institute, which develops and tries to promote drugs and services “based on cellular, gene and post-genomic technologies,” speaks of the new product as a breakthrough in science. However, many experts view the new drug differently, arguing that it is actually about “patient confusion.”

In his speech on June 3, the medical director of the Human Stem Cell Institute (HSCI), Roman Deev, noted that currently only three gene therapy drugs are registered in the world, one of which is neovasculgen, and in Europe this is generally the first gene therapy drug. “Out of 1,500 clinical trials in the field of gene therapy, about 20 are aimed at treating patients with vascular pathology, and neovasculgen has already shown its effectiveness, while some drugs have dropped out,” Deev emphasized. It seems that domestic drug manufacturers have something to be proud of! But is the new medicine really effective and safe, and how much will its use cost patients?

The Society of Evidence-Based Medicine Specialists draws attention to the fact that the Human Stem Cell Institute is not a scientific institution, but a commercial organization.

The drug created by geneticists was tested in clinics in Yaroslavl, Ryazan, and Moscow, prescribed for inoperable forms of chronic leg ischemia to patients over 40 years of age. Two injections were given. Doctors have evidence that after administering the medicine, the patient could walk without pain not 100 meters as before the injection, but up to 800 meters.

The cost of two injections is about 100 thousand rubles. “The mechanism of action of neovasculgen is based on the principle of therapeutic angiogenesis,” explained HSCI director Artur Isaev. – The drug is a circular DNA molecule that contains a region responsible for the synthesis of vascular endothelial growth factor. Local administration of the drug stimulates the growth and development of new blood vessels.” Researchers are confident that for many patients the drug can become an alternative to amputation. The percentage of “success” of therapy, according to Professor R.E. Kalinin (Ryazan Medical State University), amounted to 93.6%.

In Russia, the system of angioplasty and vascular treatment of blood vessels has not been established. What is considered “high-tech care” to prevent amputations has become routine practice in most countries many years ago.

Things are bad in Russia with medicines too. Senior Researcher at the Institute of Surgery named after. Vishnevsky Leonid Blatun says that despite the availability of advanced ointments and medicines, patients in clinics of the Russian Federation “really have access to only the most outdated means,” since modern means are not included in the standards of treatment.

How safe is neovasculgen? It must be emphasized that when a new gene is introduced into a human cell, the patient may experience cancer risks. This is why drugs with this mode of action have not previously received approval. “The theory that a researcher can act on a cell growth factor, stimulate it by introducing an autogen that will produce protein growth, is generally correct,” says Valentin Vlasov, director of the Institute of Chemical Biology and Fundamental Medicine, Academician of the Russian Academy of Sciences. – That is, with the help of genetic technology, a virus is taken and it delivers the desired gene into the cell.

On this topic

Law enforcement agencies did not initiate a criminal case against Moscow resident Elena Bogolyubova, who ordered a drug not registered in Russia by mail for her terminally ill son.

“I am familiar with the project of the Stem Cell Institute and the drug neovasculgen,” says Valentin Vlasov. – In this case, there is no question of a virus vector. I do not rule out that in a very short time after the injection, protein synthesis occurs with the help of this product, and it does not seem to bring anything bad to the patient, but whether it brings anything good, in order to assert this, a very serious evidence base is needed "

The expert noted that it is quite difficult to draw such a conclusion from the photographs provided: “How to look at them, with what resolution the X-rays were taken, how they were developed - this is all on the conscience of the researchers. It seems that small vessels are branching. The report about the drug was pompous, but I can say that if such an effect exists, it is very short in time, it can only last a few days. And there is no reason to expect a miraculous effect from the drug.” According to Academician Vlasov, scientists need to achieve long-term protein production, and this can only be achieved by “inserting” the desired gene into a cell, but researchers have not yet been able to do this safely for the patient.

Even the journal in which the results of the study of the drug neovasculgen were published looks like it belongs to the same company. According to experts, questions arise from the haste in conducting clinical trials and the lack of randomization in them (a special algorithm for conducting them that excludes interest in the results). The place of administration of the drug and its description – “plasmid construct” – raised doubts.

As a result, experts came to the conclusion that this may be a case of “consumer confusion,” since large vessels in which there is no blood flow are not restored. The researchers promised benefits for patients for two years, but the trial actually lasted only six months. The absence of declared side effects from such a drug is also suspicious. The desire of scientists to find new treatment options is not disputed. But all this requires many years of research and significant evidence before application.

Patients with critical ischemia of the lower extremities in 20–50% of cases experience so-called primary amputations, but only slightly more than half of those operated on retain both legs after a year. Every fifth person dies, and in every fourth case a “major amputation” is performed. Obviously, many patients will literally stand in line for a miracle cure. Among them there will be a huge number of diabetics.

In Russia, the number of patients with diabetes mellitus complicated by diabetic foot syndrome is about 4 million people. Such a complication in half of the cases is the main indicator for amputation. In almost half of patients, treatment for this complication begins late. At the same time, in comparison with European countries, very few low-traumatic endovascular operations on the vessels of the legs are performed in Russia. According to the Russian State Medical University. N.I. Pirogov, in EU countries 8% of complications of peripheral vessels of the legs end in amputation, while in Russia this figure is significantly higher and in diabetes mellitus reaches more than 50%. According to the President of the Russian Academy of Medical Sciences, Director of the Endocrinological Research Center of the Ministry of Health and Social Development Ivan Dedov, about 8-10% of patients with diabetes are affected by diabetic foot syndrome, and up to 50% of them can be classified as at risk. After amputations, the mortality rate of patients doubles, but if such patients are not operated on, they will die of gangrene within two years.

During surgical interventions in patients with type 2 diabetes

In type 2 diabetes there is an imbalance in angiogenesis. Diabetes is characterized by hyperglycemia and various metabolic disorders. They disrupt the balance between proangiogenic and antiangiogenic regulators and lead to inadequate formation of new vessels in diabetes mellitus (DM). In turn, disorders of angiogenesis and vasculogenesis are important mechanisms in the development of vascular complications of diabetes. Thus, the development of macrovascular complications is accompanied by suppression of the intensity of angiogenesis and vasculogenesis.
In poorly controlled diabetes mellitus (DM), the healing process of soft tissues is slowed down. In this case, one of the factors is a decrease in the level of local growth factors, which limits the possibility of building up soft gum tissue as part of implant surgery. It has also been proven that in patients with diabetes, the amount of collagen produced by fibroblasts is reduced, which leads to a slowdown in wound contraction. Impaired carbohydrate metabolism entails an increase in matrix metalloproteases (MMP) and a decrease in nitric oxide (NO), transforming growth factor beta 1 (TGFβ1), which causes a slowdown in the formation of ECM. Clinical studies show that in diabetes mellitus, angiogenesis imbalance can be achieved using both angiogenesis inhibitors and its stimulators. Stimulation of angiogenesis and vasculogenesis with the help of stem cells and growth factors is a promising direction for the treatment of insufficiency of agnogenesis in diabetes mellitus, which affects the reduction in the healing process of soft tissues and the formation of macroagniopathy.
Taking into account the above, in the postoperative period in patients with diabetes it seems promising to stimulate the process of angiogenesis due to cycotins and vascular endothelial growth factor.
It is known that vascular endothelial growth factor and cycotin stimulate angiogenesis, and thus increase tissue oxygen saturation (pO2), which is one of the factors for soft tissue repair. A decrease in the level of this growth factor leads to a slowdown in the epithelization process. Research results show that growth factors and cytokines have a decisive influence on the speed and quality of reparative processes in patients with diabetes mellitus.
So in dentistry, when growing gum tissue, implantological operations, you can use collagen membranes saturated with vascular endothelial growth factor or carry out the “Plasmodent” procedure, based on the introduction of platelet-rich plasma taken from the patient’s blood. Such plasma contains growth factors and is a stimulator of the angiogenesis process. Currently, implantological operations are performed in patients with diabetes only when the level of glycated hemoglobin is less than 6.0. This indicator is achieved by temporarily transferring the patient to insulin injections during the operation and postoperative period. However, in type 2 diabetes the patient has hyperinsulinemia due to insulin resistance. It is possible that the use of vascular endothelial growth factor to stimulate the process of soft tissue repair will allow the glycated hemoglobin indicator to shift to higher values, compensating for the disturbances of agnogenesis from hyperglycemia with vascular endothelial growth factor. It appears that the procedure for administering platelet-rich plasma can be used in any surgical procedure for patients with diabetes.

Our experts are Doctor of Medical Sciences, Professor of the Department of Hospital Surgery of the Faculty of Medicine of RUDN University Alexey Zudin and cardiovascular surgeon of the Yaroslavl Regional Clinical Hospital, Doctor of Medical Sciences, Professor of the Department of Surgery - IPDO Yaroslavl State Medical University Yuri Chervyakov.

Scale of the problem

Two million Russians suffer from ischemia of the lower extremities. The disease manifests itself as intermittent claudication - pain in the legs while walking, which does not allow a person to walk without stopping - for some more than 1 km, and for others more than 25 m. And if left untreated, the condition will only worsen.

40% of those who suffer from intermittent claudication will eventually have a leg amputation, disability, and many will die within the next 5 years after surgery. Moreover, such prospects exist not only for Russian patients, but also for patients from other countries. The frequency of amputations per 1 million population per year due to leg ischemia: 400 in Sweden, 300 in the UK, 280 in the USA, 500 in Russia.

40 thousand people are left without a leg every year. And the loss to the country’s budget per one debilitated patient is 700 thousand rubles. Here's what the problem looks like in numbers.

What is the reason?

Why does blood supply deteriorate in the legs? The disease is based on the same atherosclerosis that leads to strokes and heart attacks. Only in the case of leg ischemia, cholesterol plaques clog not large arteries, but small capillaries. The muscles do not receive enough oxygen, they begin to hurt when walking, the legs are cold, the skin on them becomes pale, the lower legs become thin due to poor nutrition, the toenails grow slowly and break...

At the same time, ischemia of the lower extremities occurs more often than other vascular diseases, such as coronary heart disease or stroke. We see 42 thousand new patients with this diagnosis every year.

How was leg ischemia treated until recently, and how is it still treated in many places now?

Vasodilator drugs are prescribed. But because they have a dangerous side effect - the risk of heart attack - such treatment is now considered ineffective.

In 30% of cases of leg ischemia, attempts are made to restore blood flow through surgery. They remove plaques from large vessels, install stents that widen the arteries, replace old vessels with artificial ones... But you cannot get into small vessels with a scalpel and you cannot place a stent in them. So for 30% of patients with leg ischemia, medicine was powerless until recently.

New method

But recently a new method has appeared: gene therapy, which allows you to grow new capillaries.

These are just 2 courses of injections, when a gene is introduced into the muscles that activates the vascular growth factor of the legs, and this factor causes the peripheral vessels to grow. Growth can continue for up to three years.

The safety of the method was confirmed during clinical studies conducted in 33 medical institutions in Russia and Ukraine. Starting this year, the drug created by our scientists, registered and produced in Russia, is included in the list of vital drugs.

Six years have passed since the first patients received gene therapy and grew new capillaries. So they remained, supplying the tissues of the legs with blood and allowing former patients to walk without pain.

Risk factors for developing coronary leg disease:

1. Age: atherosclerosis of the vessels of the legs in men begins to appear after 45 years, in women - after 55 years;

2. Male gender;

3. Smoking: 90% of patients with leg ischemia are heavy smokers;

4. Diabetes: Patients with this disease are 10 times more likely to undergo amputation;

5. Obesity: the risk of atherosclerosis increases if a man’s waist circumference is more than 102 cm, and a woman’s is more than 88 cm;

6. Hypertension;

7. High cholesterol levels in the blood: this is a risk factor for the appearance of plaques that clog blood vessels;

8. Heredity: at risk are those whose relatives have had heart attacks and strokes.

For 30 years, it has been suggested that angiogenesis, the process of formation of new blood vessels, could become an important target for anticancer therapy. And only recently this opportunity was realized. Clinical data have demonstrated that the humanized monoclonal antibody drug bevacizumab, which targets a key proangiogenic molecule, vascular endothelial growth factor (VEGF), can prolong the life of patients with metastatic colorectal cancer when administered as first-line therapy in combination with chemotherapy drugs. Here we discuss the functions and significance of VECF to demonstrate that VEGF is a reasonable target for anticancer therapy.

What is VEGF?

VEGF is one of the members of a family of structurally related proteins that are ligands for the VEGF receptor family. VEGF influences the development of new blood vessels (angiogenesis) and the survival of immature blood vessels (vascular support) by binding to and activating two closely related membrane tyrosine kinase receptors (VEGF receptor-1 and VEGF receptor-2). These receptors are expressed by endothelial cells in the wall of blood vessels (Table 1). The binding of VEGF to these receptors initiates a signaling cascade that ultimately stimulates vascular endothelial cell growth, survival, and proliferation. Endothelial cells are involved in such diverse processes as vasoconstriction and vasodilation, antigen presentation, and also serve as very important elements of all blood vessels - both capillaries and veins or arteries. Thus, by stimulating endothelial cells, VEGF plays a central role in the process of angiogenesis.

Why is it important to do Vascular Endothelial Growth Factor (VEGF human)?

VEGF is extremely important for the formation of an adequately functioning vascular system during embryogenesis and in the early postnatal period, but in adults its physiological activity is limited. Experiments on mice showed the following:

• Targeted damage to one or two alleles of the VEGF gene leads to the death of the embryo
• Inactivation of VEGF during early postnatal development is also fatal
• Damage to VEGF in adult mice is not accompanied by any obvious abnormalities because its role is limited to follicular development, wound healing, and the reproductive cycle in females.

The limited importance of angiogenesis in adults means that inhibition of VEGF activity represents a feasible therapeutic goal.