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Vol 15, No 1 (2020)

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Open Access Open Access
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Gene therapy in regenerative medicine: latest achievements and actual directions of development

Slobodkina E.A., Karagyaur M.N., Balabanyan V.Y., Makarevich P.I.


Gene therapy is a group of methods for treatment of various groups of diseases by replacement of damaged, introducing new genes or changing their expression. This is a new and actively developing area in biomedicine. Approaches to regulation of gene therapy drugs at all stages - from production, preclinical and clinical trials, as well as registration and marketing approval are not fully developed and regularly updated. This article provides an overview of worldwide approaches to conducting studies of gene therapy drugs and the procedures for their "accelerated registration”. This article as well summarizes our experience of Lomonosov Moscow State University in development of new direction vectors - gene therapy for the delivery of several therapeutic proteins. In the near future, this approach can be used to increase the effectiveness of gene therapy for stimulating vascular and axon growth, and tissue regeneration.
Genes & Cells. 2020;15(1):6-16
pages 6-16 views

Tay-Sachs disease: diagnostic, modeling and treatment approaches

Solovyeva V.V., Shaimardanova A.A., Chulpanova D.S., Kitaeva K.V., Rizvanov A.A.


Tay-Sachs disease (OMIM 272800) belongs to the group of autosomal-recessive disorders, caused by p-hexosaminidase A (HexA) enzyme deficiency, resulting in GM2-ganglioside accumulation in nervous and other tissues of the body. Enzyme deficiency is caused by various mutations in HEXA gene. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, there is no effective treatment for Tay-Sachs disease. There are clinical reports of substrate reduction therapy, bone marrow or umbilical cord blood transplantation. However, the therapeutic efficacy of these methods remains insufficient to prevent aggravation of neurological symptoms in Tay-Sachs disease patients. Encouraging results were obtained using gene therapy to deliver wild-type genes encoding the а and p subunits of HexA. This review discusses the therapeutic strategies in Tay-Sachs disease treatment, as well as diagnostic methods and existing animal models to evaluate the effectiveness of new approaches for Tay-Sachs disease therapy.
Genes & Cells. 2020;15(1):17-22
pages 17-22 views

Neuro-immune interactions in cholinergic antiinflammatory pathway

Tuchina O.P.


More and more researches suggest that the nervous and immune systems actively interact. Investigation of the mechanisms that underlie the development of septic shock led to discovery of a qualitatively new type of neuro-immune interactions - the cholinergic anti-inflammatory pathway involving the vagus nerve. However, despite the electrical stimulation of the vagus nerve that is already actively used in order to relieve the symptoms of some autoimmune conditions, many molecular and cellular aspects of the cholinergic anti-inflammatory pathway remain unknown or controversial. This review discusses the mechanisms of the reception of inflammatory mediators by vagal afferent fibers and nervous cells in the area postrema, the nerve centers presumably involved in the processing of immune information, the efferent parasympathetic effects on the immune system, in particular, the release of pro-inflammatory cytokines by spleen macrophages, as well as the role of cholinergic anti-inflammatory pathway in maintaining homeostasis in the body.
Genes & Cells. 2020;15(1):23-28
pages 23-28 views

Generation and characterization of human emryonic stem cells with increased expression of HIF-2a

Zhiven M.K., Zakharova I.S., Shevchenko A.I., Elisaphenko E.A., Orishchenko K.E., Zakian S.M.


The HIF-2 a subunit is involved in regulation of transcription factors, controlling the self-renewal of human pluripotent stem cells, embryonic development of the cardiovascular system and the regulation of angiogenesis by transcriptional activation of angiogenic cascades in physiological and pathological processes. Currently, modulation of HIF-2a expression is considered as a promising strategy for the treatment of ischemic and cancer diseases. However, the problem of choosing the optimal methods of effective regulation of HIF-2a remains. The aim of this study is to obtain human embryonic stem cells with increased expression of HIF-2a at normal oxygen concentration due to silencing of INT6, the regulator of HIF-2a. In this study, we obtained genetically modified human embryonic stem cells with increased expression of HIF-2a under atmospheric oxygen conditions. The approach used is based on a CRISPR/Cas9-mediated deletion of a part of the INT6 gene, an HIF-2a inhibitor. A study of the resulting genetically modified human embryonic stem cells will contribute to an understanding of the connection between hypoxia and pluripotency. Obtaining endothelial derivatives of pluripotent stem cells with increased expression of HIF-2a and enhanced regenerative potential may become the basis for the development of promising strategies for treatment of ischemic diseases.
Genes & Cells. 2020;15(1):29-36
pages 29-36 views

Nonmyeloablative bone marrow cells transplantation restores dystrophin synthesis in the muscles of MDX mice

Sokolova A.V., Timonina N.A., Kravtsova V.V., Krivoi I.I., Skripkina N.S., Kaminskaia E.V., Mikhailov V.M.


Duchenne muscular dystrophy is an X-linked recessive muscular dystrophy associated with a mutations in the dystrophin protein gene. The most common laboratory model of Duchenne muscular dystrophy is mdx mice. The striated muscle fibers of mdx mice are characterized by the absence of dystrophin, the presence of centrally located nuclei, and the high level of renewal of the striated muscle fibers. In addition, mdx mice show a morphological aberrations at neuromuscular junctions, expressed in the breakdown of large clusters of acetylcholine receptors in the form of branches into small clusters in the form of islets. One approach to treating muscular dystrophy in mdx mice may be the nonmyeloablative transplantation of wild-type bone marrow cells after X-ray irradiation of mdx mice at a dose of 3 Gy. The aim of this work is to evaluate the effect of nonmyeloabla-tive transplantation of wild-type bone marrow cells on dystrophin synthesis and the structure of neuromuscular junctions of mdx mice. Mdx mice were irradiated with X-rays at a dose of 3 Gy, after 24 hours was performed intravenous transplantation of bone marrow cells of C57BL/6 mice. The m. quariceps femoris and diaphragm were examined 2, 4, 6, 9, 12 months after transplantation. Muscle studies were performed using immunohisto-chemical methods of study (immunohistochemical staining with antibodies to dystrophin). The neuromuscular junctions were stained with tetramethylrodamine-a-bungarotoxin. After intravenous bone marrow cells transplantation, the part of dystrophin-positive muscle fibers in the muscle quadriceps femoris was shown to increase to a 27,6±6,7% 6 months after transplantation. After 12 months, the part of dystrophin-positive muscle fibers decreased to 5,1±1,1%. There was also an increase in the proportion of striated muscle fibers without centrally located nuclei and a decrease in the part of dead striated muscle fibers. Similar changes were found in the striated muscle fibers of the diaphragm of mdx mice. In addition, transplantation of bone marrow cells after irradiation at a dose of 3 Gy increases the part of neuromuscular junctions with normal structure. Thus, nonmy-eloablative transplantation of wild-type bone marrow cells can be considered as one way to treat monogenic disease of striated muscle fibers muscular dystrophy of mdx mice.
Genes & Cells. 2020;15(1):37-44
pages 37-44 views

Cytotoxic and genotoxic effects of mitomycin C toward human endothelial cells

Sinitsky M.Y., Kutikhin A.G., Shishkova D.K., Asanov M.A., Ponasenko A.V.


Mitomycin C is the most used for in vitro mutagenesis modeling alkylating agent belonging to the single-site mutagens. In the presented study, the in vitro cytotoxic and genotoxic effects of mitomycin C in endothelial cells of different arteries differ in the level of atherogenesis were studied. MTT colorimetric assay was used for assessment of cytotoxicity of different concentrations of mitomycin C, cytokinesis-block micronucleus assay - for estimating of genotoxic effects in human coronary and internal thoracic artery endothelial cells exposed to mutagen. After 6-h cultivation no decrease in the viability of cell cultures exposed to all studied concentrations of mitomycin C was observed; an increasing time of mutagenic load to 24 hours resulted in a significant (p<0,05) decrease in the number of viable human coronary- and internal thoracic artery endothelial cells at concentrations of mitomycin C above 350 ng/mL and 200 ng/mL, respectively. Exposed cultures are characterized by three-fold increasing of cytogenetic damages (micronucleus, nucleoplasmic bridges and nuclear buds) compared to control (p<0,01); the cells of internal thoracic artery have a higher level of DNA lesions in comparison to coronary artery. Thus, endothelial cells of different arteries differ in the threshold of sensitivity to cytotoxic exposure of alkylating agents and the manifestation of genotoxic effects of mitomycin C.
Genes & Cells. 2020;15(1):45-49
pages 45-49 views

Features of DNA repair in dermal fibroblasts in ataxia-telangiectasia patients with mosaic type of manifestation of active ATM kinase

Kuranova M.L., Nozdracheva A.V., Ushakov R.E., Ledashcheva T.A., Schugareva L.M., Maklanova E.A., Manenok Y.N., Vasilishina A.A., Pleskach N.M., Spivak I.M., Mikchelson V.M.


Cell mosaicism is found in biological systems much more often than clinically identified forms of the disease, in some cases, "erased forms” or "normal variants” are phenotypic manifestations of mosaicism. Some diseases, difficult for a clinical diagnosis, such as ataxia-telangiectasia, are based on cell mosaicism. This work is aimed to study DNA repair disorders in the cell lines of dermal fibroblasts isolated from skin biopsies of 5 patients with a clinically diagnosed ataxia-telangiectasia. In the obtained cell lines, the method of indirect immunofluorescence was used to determine the number, intensity, focus area pATMSer1981 and 53BP1, as well as the number of cells with the active form of the ATM kinase. The mosaic pattern of malfunctioning of the active form of the ATM kinase, phospho-ATM Ser1981, was revealed at different time intervals after exposure to ionizing radiation at a dose of 2 Gy. Significant differences were found between the number of ATMSer1981 and 53BP1 foci, the fluorescence intensity and their area in the cells of patients with ataxia-telangiectasia and healthy donors. The results of this work can be used in the diagnosis of ataxia-telangiec-tasia and determining the degree of impairment of the functional activity of the ATM gene.
Genes & Cells. 2020;15(1):50-59
pages 50-59 views

Osteogenesis in epitelial tumors on the example of a pilomatricomas

Deev R.V., Plaksa I.L., Baranich A.V., Shcherbakova E.V., Vinogradov I.I.


Heterotopic osteogenesis (HO) is the process of formation of typical bone tissue in a place in the body where this tissue normally does not develop. HO can be the outcome of many pathological processes, for example, necrosis, the organization of hematomas and primary tuberculous affect, and also develop in tumors of various histogenesis. This may be an example of the mutual induction of tissue development in an adult organism. Pilomatricoma (epithelioma of Malherbe) is a rare benign tumor, accounting for 0,2% of all skin neoplasms, developing from the hair follicle epithelium. In rare cases, foci of HO can be detected in the tumor structure. 43 cases pilomatricomas were analyzed by, in 3 (7%) of which bone tissue was detected. Histological and immunohistochemical studies and clinical morphological analysis were performed.
Genes & Cells. 2020;15(1):60-65
pages 60-65 views

Bioresorption and biodegradation of the 3D-printed gene-activated bone substitutes based on octacalcium phosphate

Presnyakov E.V., Bozo I.Y., Smirnov I.V., Komlev V.S., Popov V.K., Mironov A.V., Deev R.V.


Gene-activated materials are getting translated to the clinical practice that is the result of increased research activity in this area. There is significant success in development of gene-activated materials for bone grafting procedures. In our study, we made the gene-activated bone substitute based on octacalcium phosphate and plasmid DNA with VEGFA gene using three-dimensional printing technologies (discs, size of 10x2 mm). During the subcutaneous test in rats, the dynamics of bioresorption of materials was evaluated in comparison with the control that was presented by the scaffold without gene constructs. 60-90 days after surgery, volumes of the implants twicely decreased while the diameter declined by 20% at 180 days, and there were no significant differences between the groups related to these parameters. According to a histological examination, no signs of pronounced inflammation were found in the operation zone, the materials were surrounded by a connective tissue capsule. Further studies are needed to evaluate the effect of gene-activated materials produced with the developed technology on reparative osteogenesis.
Genes & Cells. 2020;15(1):66-70
pages 66-70 views

Pathomorphologic characteristics of venous vessels after the application of different methods of endovascular eliminating of venous reflux - experimental study

Abrosimova T.I., Kurmanskii A.V., Borisov A.A.


Varicose veins have been the subject of a recent technologies of nontumescent treatment that outline the safety and effectiveness questions concerning proposed obliteration methods. The goal of this study is to analyze changes in the venous wall structure appearing as a result of using thermal tumescent and nonthermal nontumescent methods in compare. Methods: microscopic investigation of vein specimens of adult sheep (n=9) performed on 1, 7 and 100 day after procedure to determine the grade of damage and inflammation. Results: On the 1st and 7th days after the use of endovenous laser, endothelial destruction was 100%, with total depth damage of vein wall and total destruction of the elastic carcass, also traces of carbonization on the first and vaporization on the seventh day have been seen. In a result of the use of nonthermal method, there was a residual endothelium up to 30%; with the use of cyanoacrylate glue - up to 10%. In the long-term period of observation, glue masses undergo a sewage process and is preserved as separate lumps, there is an abundance of multicore macrophages with fragmented glue in the cytoplasm. Conclusion: the results allow us to consider nonthermal nontumescent methods as a possible alternative to thermal methods available in clinical practice.
Genes & Cells. 2020;15(1):71-77
pages 71-77 views

Regulation of the reserch and development of cellular drugs: the experience of the European Union and the United States

Niyazov R.R., Dranitsyna M.A., Yasny I.E., Gavrishina E.V., Vasiliev A.N.


In the European Union and the United States, regulation of cell-based products for the placing on the market is rather extensive and multi-tiered. This is due to the complexities which emerge at the different steps of the process, e. g. when obtaining source materials (live human cells), further development, manufacturing and clinical investigation, as well as due to risks posed by cellular products for the patient and other people. In this paper we address foreign regulatory systems for products containing live cells as an active ingredient in order to establish the difference with the domestic system.
Genes & Cells. 2020;15(1):78-87
pages 78-87 views

Pravila dlya avtorov

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Genes & Cells. 2020;15(1):88-90
pages 88-90 views

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