How to treat cardiovascular diseases?
Modern methods of CVD treatment – cell and gene therapy
Despite the wide range of surgical possibilities, cardiovascular diseases (CVD) are the most common cause of death among the world's population. Currently, they affect about 8% of the Russian population, and mortality from vascular complications is 53% of all deaths. A significant proportion of deaths are due to coronary heart disease (CHD) and critical lower limb ischemia (KINK). In particular, the risk of amputation in patients with KINK exceeds 20%, and 30% of them will die within the first month after amputation.
This situation forces us to look for new methods of treating these diseases, and one of the most promising methods is therapeutic angiogenesis, which allows improving the blood supply to the affected tissues of the heart or extremities due to the growth of new blood vessels. Currently, there are three areas in which research or treatment in this area is being conducted: the use of recombinant proteins, cellular and gene therapy.
Recombinant proteins
According to Nina Mzhavanadze, an employee of the Department of Angiology, Vascular, Operative Surgery and Topographic Anatomy of the Ryazan State Medical University. Academician I.P. Pavlova, the main research in the direction of postgenomic technologies is devoted to recombinant proteins -growth factors VEGF 165, FGF 1, FGF 2, as well as hepatocyte growth factors. Unfortunately, studies of FGF1 and FGF2 factors did not give the desired results, which, apparently, is due to their rapid decomposition in the bloodstream. Studies of VEGF proteins also did not give a significant positive effect, so today additional research is needed in this direction.
Cellular technologies
A more promising method of modern therapy is cellular technologies for the induction of angiogenesis, and their use in the treatment of coronary heart disease seems to be the most effective. The main objects of research for clinical therapy are progenitor endothelial cells and multipotent mesenchymal stem cells, which are highly effective in creating growth factor proteins. The possibilities of adipose tissue stem cells with the ability to transform into endothelial cells and produce several types of similar proteins are being actively studied. Finally, a number of researchers are developing techniques for autogenic cell transplantation of single-core bone marrow and blood cells.
In the early 2000s, scientists made active attempts to use skeletal muscle tissue embryos, but the research was unsuccessful, and now this type of therapy is not used. But placental cells isolated from umbilical cord blood showed good results in the treatment of lower limb ischemia. Currently, clinical studies are underway on the efficacy and safety of this type of therapy. In addition, clinical trials of endometrial regenerative cells that promote revascularization of ischemic muscles of the lower extremities are being conducted.
But obtaining cell therapy drugs is a complex process and requires specific equipment, since the drugs are produced from the patient's own punctate, that is, there are certain difficulties in obtaining enough material for clinical purposes. Also, a significant number of cells die quickly after transplantation. Finally, there are a number of organizational and economic difficulties. All these factors prevent the introduction of cell therapy into a wide clinical practice. In this regard, research in the direction of gene therapy, which is able to solve problems inaccessible to cellular technologies, is becoming more relevant.
Gene technologies
Olga Demidova, an employee of the Bakulev Scientific Center for Cardiovascular Surgery, said that studies of the effect of gene technologies on the course of lower limb ischemic disease were started in 1981, when a gene drug was first introduced to the patient. Two years later, nine cases of gene therapy with good clinical results were described, and among the treated patients there were patients with II and . In Russia, such studies have been conducted for 13 years, and some of them have been conducted at the Institute. Bakuleva under the guidance of Academician Leo Bokeria.
Currently, the center named after Bakuleva has the results of 12-year studies of therapy with the VEGF 165 inducer drug, which showed a high percentage of patient survival and limb preservation in patients with KINK.
As the Director of Science of the Institute of Human Stem Cells (ISCH) Roman Deev said, in 2011, Professor of the Russian Cardiological Research and Production Complex Elena Parfenova and co-authors presented the results of their clinical study conducted with the participation of 30 patients with chronic lower limb ischemia. Patients were injected with a plasmid DNA-based construct including the coding part of the VEGF 165 gene with the working name "Corvian". As a result of the experiment, the growth of collateral vessels and improvement of blood patency in the affected limb was noted in 50% of patients.
Academician of the Russian Academy of Sciences Nikolai Bochkov and specialists of the Russian Scientific Center of Surgery named after B.V. Petrovsky Alexander Gavrilenko and Dmitry Voronov performed a number of works devoted to the study of viral gene therapy structures carrying VEGF and (or) ANG genes in the complex treatment of patients with HINK.
In turn, the researchers of the Surgery Center named after Academician B.V. Petrovsky conducted an analysis of the effectiveness of genetically engineered complexes for stimulating angiogenesis based on endothelial growth factor genes, in which the results of 10-year observations were systematized. According to the vascular surgeon of the center Evgeny Oleinik, such constructions proved to be effective both in combination with operations and with conservative therapy. Moreover, the use of these designs improved the long-term results. According to Oleynik, the achieved effects persist for ten years or more, while remaining safe for all groups of patients.
In 2013, a team of specialists from Kazan Medical University presented the results of a pilot clinical study of the use of a complex plasmid structure carrying the VEGF and bFGF genes for the treatment of chronic lower limb ischemia. According to the study, six months after the use of the two-cassette plasmid vector pBud-VEGF165-FGF2, the intensity of blood circulation in the lower extremities increased by an average of 19%.
Another widely studied group of genes are inducers of FGF and HGF proteins. The phase II clinical trial of the HGF-based drug in patients with KINK revealed positive results in 70% of cases. The results of recent clinical trials have not yet been published, but it can already be concluded that FGF and HGF agents are more promising in the treatment of coronary heart disease, while the genes responsible for the synthesis of VEGF and SDF are more effective against HINK.
Neovasculgen
The first example of the completion of the entire cycle of preclinical and clinical studies was the work on the introduction of the Neovasculgen drug developed by the HSCC. According to Igor Plaksa, a researcher at the ISKCH, the active component of Neovasculgen is a plasmid containing the VEGF 165 gene, which encodes the synthesis of a protein – vascular endothelial growth factor. In muscle cells, the plasmid expresses the endothelial growth factor gene, which, in turn, increases the concentration of endogenous factor. The development of collateral vessels begins, and, as a result, the improvement of blood microcirculation in the muscle.
According to Ilya Staroverov, head of the Department of Surgery of the EITI Yaroslavl Medical Academy, the cost of Neovasculgen is quite high, but the methods of genetic engineering are generally very expensive and such drugs should be guided by state support. But if we consider that the only alternative to treatment is amputation of the patient's limb, the economic advantage of using the drug is beyond doubt. Three quarters of the patients who underwent therapy at the Yaroslavl Regional Clinical Hospital had an improvement in the condition of their limbs. Several patients could not be helped, however, this was due to the fact that patients were admitted to treatment already in a state of KINK, that is, with pronounced gangrene. The surgeon explained that it takes at least a month for the effect of therapy to manifest, and in some cases the gangrene has already spread so much that there simply wasn't enough time to resume blood flow.
Roman Deev noted that studies of the drug were completed in 2011, after which the Ministry of Health included it in the State Register of Medicines. Since 2012, the use of Neovasculgen in routine practice has begun. Currently, the HSCC has received permission from the Ministry of Health of the Russian Federation to conduct clinical trials in patients with diabetic foot syndrome, in which the efficacy and safety of the drug for this group of patients will be evaluated. The study, which will involve 99 patients, will last until March 1, 2018.
Technology efficiency
As explained by Alexey Zudin, professor of the Department of Hospital Surgery of the RUDN, it is impossible to say that cellular technology is an absolutely effective method of treating cardiovascular diseases - this opinion was expressed by participants of the congress devoted to the rehabilitation of people with heart pathology, which was held this spring in Switzerland.
Currently, cell therapy is used quite confidently, concluded Zudin, but it is practiced in a small number of medical centers around the world. Gene therapy is currently used mainly for lower limb ischemia. In addition, experiments are underway to introduce genetic material by coronary angiography into the heart muscle, but they have not yet gone beyond the scope of research.
According to Olga Demidova, a combination of gene and cell therapies may become a promising direction in new methods of CVD treatment. One of the variants of this combination is the genetic modification of cellular material, implying the processing of bone marrow with subsequent autotransplantation, which allows to dose the therapeutic effect and increases the viability of the transplanted cells. The second option is the preliminary introduction of genetic material before autotransplantation for tissue preconditioning. Both of these methods are currently being investigated on the myocardium, and the first promising results have already appeared in experiments in the first direction.
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07.12.2016