Gene and cell therapy in Kazan

KFU plans to bring the developed methods of gene and cell therapy to the All-Russian level

Natalia Doroshkevich
Institute of Fundamental Medicine and Biology 
89503297172 natalia_doroshkevich222@mail.ru

Published on the website Press-release.ru

A seminar was held on the territory of the Republican Clinical Hospital, which was attended by researchers of the IFMiB KFU, doctors of the university clinic and the RCB.

The reason for the meeting was the need to summarize the results of joint experimental work over a fairly long period of time – from 2010 to 2016.

I must say that the long-term cooperation of KFU–RCB, according to clinicians who presented at the seminar the results of the use of the technology developed by KFU scientists in the clinic, has already helped dozens of people to cope with particularly complex manifestations of diseases requiring stimulation of regenerative processes in the body - with post-traumatic defects of peripheral nerves, diseases of peripheral arteries, post-traumatic and degenerative-dystrophic lesions bones and large joints of the lower extremities.

Director of the Institute of Fundamental Medicine and Biology of KFU Andrey Kiyasov, speaking to colleagues, recalled how it all started – in 2007, the republican program for the development of cellular technologies in the Republic of Tatarstan was initiated. It was then that the RCB began conducting pilot studies on the safety and effectiveness of the use of blood cells for the treatment of liver fibrosis and arterial diseases of the lower extremities.

The program has been developed with the involvement of traumatologists and microsurgeons in the work.

Currently, the development of gene-cell technologies that stimulate regenerative processes in the body is carried out on the basis of the Institute of Fundamental Medicine and Biology of the KFU and the REC of Pharmacy, created for the development and testing of medicines within the framework of the Federal Target Program Pharma-2020.

The structure of the REC of Pharmacy includes several bases and calving – medical chemistry, exploratory research, preclinical research, clinical research, facilities for keeping laboratory animals, etc.

As you know, both the Institute and the REC of Pharmacy, the university clinic are part of the structure of the strategic academic unit of the university "Translational 7P Medicine", the purpose of which is to broadcast the results of scientific activity to the clinic, the implementation of the so–called strategy "from the laboratory table to the patient's bed". It is assumed that gene-cell therapy will be available to patients of the university clinic.

In addition, with the entry into force of the new law on cellular technologies, KFU is preparing to fully certify all its innovative products in accordance with the new legislation.

For this purpose, in particular, a corresponding base was created at 18 Volkova St., where the center for cellular technologies, a biobank and a clinical diagnostic laboratory of the MSCH of KFU are located.

It is important to note that research is conducted at KFU under the permission of the local ethics committee of the university, and on a number of scientific topics carried out by the RCB, funded by the Ministry of Health of the Republic of Tatarstan.

During these years, significant scientific results have been obtained at KFU, which have been confirmed to be effective in clinical conditions. All of them were timely covered on the university's website:

• KFU scientists have proposed using a combined gene-cell method in the treatment of spinal cord injuries;
• KFU scientists have successfully applied a combination of two genes in the therapy of spinal cord injuries;
• The first pilot production of gene preparations in Russia is being created in KFU;
• KFU scientists have received positive results of treatment of ischemia and peripheral nerve injuries;
• KFU scientists have taken a step towards victory over neuromuscular diseases;
• The gene therapy of pseudoarthrosis created by CFU scientists has been successfully tested in the clinic.

Albert Rizvanov, Head of the Research Institute of Gene and Cell Technologies of the IFMiB of the KFU, Corresponding Member of the Academy of Sciences of the Republic of Tatarstan, told in more detail about the essence of gene and cell therapy, what work was carried out at KFU, what are the global trends in this area. For a detailed understanding of the issue, we present it in full:

– Gene therapy is a set of methods used to carry out targeted changes in the genetic apparatus of cells, this can happen both for the purpose of correcting mutations, for example, for the treatment of hereditary diseases, and, in principle, for the treatment of other diseases. For example, what we do in the RKB, first of all, has the task of increasing the level of regeneration. And instead of correcting some defects, we, on the contrary, introduce an additional function of a particular gene responsible, for example, for the synthesis of growth factors, which leads to the stimulation of angiogenesis (the process of formation of new blood vessels in an organ or tissue) and neuroprotections.

Four genetic medicines approved for clinical use have been registered on the world market today, and another one is at the final stage of registration.

The first two Chinese–made drugs are oncolytic adenoviruses aimed at the treatment of head and neck tumors

In 2011, a Russian drug was registered – the third in the world, the first in its class and in Europe, developed on the basis of plasmid DNA expressing vascular growth factor for the treatment of lower extremities. Another drug was relatively recently registered in the EU – for the treatment of one of the hereditary metabolic diseases.

Another antitumor drug is currently at the stage of registration in the USA.

We have a real chance to enter into global competition in the global market and try to introduce our gene therapy technologies into clinical practice.

In general, gene therapy can be divided into two types. This is a direct one when a genetic construct is injected directly into the patient's body. And also cell-mediated gene therapy, or gene-cell therapy, when the cells of a patient or donor during allogeneic transplantation are genetically modified to give them additional properties – either this is a correction of mutation, or overexpression of therapeutic genes. The design is introduced into the patient's body already in the form of a gene-cell preparation.

Gene therapy can be divided into two main approaches used – viral and non-viral nature. They differ from each other, first of all, in the balance of efficiency and safety. Viral therapy is highly effective, but at the moment it has safety issues. Non-viral therapy is relatively safe, currently there are no publications where any side effects have been shown. However, the effectiveness of non-viral therapy is lower.

The use of retroviruses is one of the ways to deliver genetic material to the patient's body. We know that viruses have co-evolved for tens of millions of years together with eukaryotes, having worked out an ideal mechanism for the penetration and delivery of their genetic material into the cell. Well, the scientists of the world have learned how to use viruses to deliver the gene that is necessary to provide a therapeutic effect. The disadvantage is that in this case there is a danger of insertion mutagenesis, and this, in turn, means that there is a danger of oncological transformation. Thus, despite all the advantages of the high efficiency of delivery of this method to the body, the long-term expression of the transgene and the ability to carry a sufficiently large insert with a large amount of genetic information, integration into the genome is a serious negative factor, as it contributes to the emergence of the problem of oncological safety.

There are also problems with the use of adenoviruses. This is a different type of virus. It also provides effective delivery, medium-duration expression, however, the first generations of adenoviruses had problems related to immunogenicity, could cause undesirable adverse immune reactions. Although, I must say that in modern developments, these problems are gradually fading into the background.

One of the types of non-viral gene therapy are bacterial cell plasmids, that is, small DNA molecules, extra-chromosomal genetic elements of a bacterial cell and are double-stranded ring molecules.

An example of one of the designs used in our research: with the help of molecular scissors, the ring plasmid is cut and some of its parts are replaced by genes of interest to us. In our case, attention is paid to proangiogenic growth factors, as well as neuroprotective, neurotrophic, supporting axon survival.

The main advantage of the design is the absence of immunogenicity, integration into the genome. In addition, they are cancer-safe. It is important to say that short-term transgene expression can be considered both a plus and a minus. From the point of view of regenerative medicine, it is quite possible that this is a plus. There is no need for constant stimulation of vascular growth, this is necessary only during the period when it is necessary to start the regeneration process, then this process stops, the body's natural ability to regenerate comes into play. If we have constant angiogenesis in the area of drug administration, it will not lead to anything good.

The apparent problem is also the low efficiency of gene transfer or transfection into the cell. How many copies of genes can we deliver? It is important that even small amounts, but targeted delivered, can have a sufficient therapeutic effect, helping the natural processes of regeneration in the body.

Another area of regenerative medicine is cell therapy – transplantation of human cells, both autologous (using patient cells) and allogeneic – from a donor – for the treatment of various pathologies. And, of course, one of the rapidly developing areas is stem cell transplantation. The most commonly used types of stem cells in the clinic are mesenchymal. They can be obtained from bone marrow, adipose tissue, placenta, umbilical cord. Also hematopoietic stem cells. Another type is induced pluripotent stem cells, which have characteristics similar, if not identical, to embryonic stem cells. They cannot be used directly, but since they are pluripotent, that is, capable of differentiation in almost all directions, giving rise to almost any cells of the body, from them, as from blanks, it is possible to obtain cellular material for subsequent clinical use.

In our practice, we use cells of the stromal-vascular fraction of adipose tissue rich in mesenchymal stem cells, fibroblasts, endothelial cell precursors and various immune cells that have, among other things, an anti-inflammatory effect. The fraction is rich in cells that can stimulate angiogenesis, they themselves can participate in the formation of new capillaries and blood vessels, secrete various growth factors that have, among other things, neuroprotective, neurotrophic effects. One of the methods of application is the isolation of a stromal-vascular fraction from adipose tissue, which is mixed with adipose tissue. All this together resorbs much worse after transplantation due to actively occurring vascularization processes. For cosmetic procedures, this approach is effective. The fraction can also be used in various clinical applications.

List of papers presented at the seminar:

1. The experience of implementing joint scientific and practical work of KFU and RCB in clinical practice "from laboratory to clinic", prospects for development. Speaker: D.B.N., Prof. Rizvanov A.A.;
2. Gene and cellular technologies in peripheral nerve regeneration. Experimental model. Speakers: PhD Masgutov R.F., PhD Masgutova G.A.;
3. Gene-activated bone graft in bone tissue regeneration. Experimental model. Speaker: Zhuravleva M.N.;
4. New therapeutic forms of collagen and its derivatives for tissue regeneration. Speaker: Ph.D. Abdullin T.I.;
5. Development of new methods of treatment of patients with post-traumatic peripheral nerve defects and brachial plexus injury. Speaker: MD, Prof. Bogov A.A.;
6. Development of new combined methods of treatment of patients with combined limb injuries. Speaker: PhD Mullin R.I.;
7. Improvement of methods of treatment of patients with peripheral artery disease based on direct gene therapy. Speakers: Doctor of Medical Sciences Maximov A.V., Candidate of Medical Sciences Plotnikov M.V.;
8. Improvement of methods of treatment of patients with posttraumatic and degenerative-dystrophic lesions of bones and large joints of the lower extremities. Speaker: Candidate of Medical Sciences Masgutov R.F.

Portal "Eternal youth" http://vechnayamolodost.ru  03.02.2017