Gene Therapy knocks on the door

Expert Alexander Prokofiev: "We are on the verge of a boom in gene therapy drugs"

Alexander Alekseenko, "Express-News"

Alexander Prokofiev, head of the department for the development of viral vectors of the biotech company BIOCAD, spoke at an introductory lecture during the global popular science campaign "Open Laboratory 2020" about what gene therapy is and why modern medicine should be engaged in this area.

For many incurable hereditary diseases, no effective treatment has yet been invented. For example, from hemophilia. Patients with this disease, depending on the severity of the condition, are forced to receive an injection of recombinant proteins every week that restore the function of blood clotting. These are expensive and painful injections, which, unfortunately, do not lead to a cure for the disease. And there are diseases for which, in principle, there is no therapy and the gene therapy approach is the only way of therapy today. Many severe oncological diseases have high resistance to standard chemotherapy and treatment with protein preparations. The development of gene therapy approaches will help to create effective drugs for the treatment of such patients. And, of course, the focus of attention is not only such socially significant diseases as HIV infection, diabetes mellitus, but also severe neurodegenerative diseases against which there are no effective drugs yet. In fact, with the help of gene therapy approaches, these diseases can be cured, and not just offer supportive therapy. A single injection with a gene therapy drug can replace lifelong therapy.

The essence of gene therapy drugs, as this term is defined in the law of the EAEU, is to deliver a section of nucleic acid, either DNA or RNA into cells. These delivery vehicles must get into the right tissues and provide reliable protection of the nucleic acid. Nature has already given us such tools, viral particles. Viruses are created by nature to deliver nucleic acid to cells. What is a virus? This is a protein capsule containing a fragment of genetic information. In the normal life cycle of a virus, it enters the cell, releases its DNA/RNA, and new viral particles are produced in the cell.

Accordingly, scientists took advantage of this mechanism of nature and made modified or recombinant viral particles based on various viruses that cannot multiply in the human body and cause pathogenic conditions. But they can deliver the genome to the target cells. Different viral particles are used depending on what effect and what type of gene therapy needs to be provided. For example, adeno–associated viruses are the least immunogenic viral particles and they can be used for gene therapy in vivo - that is, simply inject recombinant viral particles to a person to deliver a therapeutic gene. This is an absolutely safe way. And there are viral particles that can be used for an ex vivo approach, when cells are modified and then these modified cells are injected into the patient to achieve a therapeutic effect.

Gene therapy drugs are a relatively new direction in the biotechnology industry. Advanced therapy medicinal products is translated into Russian as advanced therapy drugs, and represent innovative drugs for medical use based on gene therapy (gene therapy medicines), cell therapy (somatic-cell therapy medicines) and tissue-engineered products (tissue-engineered medicines).

The main difference between gene therapy drugs is that with a single use, complete recovery of patients from previously considered incurable diseases, including cancer, is possible. Currently, gene therapy is one of the most expensive, but there is reason to believe that over time, treatment with gene therapy drugs will become available to a wide range of patients.

The first success of gene therapy occurred in the early 1990s, when a group of researchers led by Professor Andersen received permission to conduct a clinical trial for the treatment of severe combined immunodeficiency associated with deficiency of the enzyme adenosine deaminase (ADA-SCID). We are talking about the so-called "bubble boy disease", or "bubble boy syndrome". This is a severe hereditary disease associated with serious disorders in the immune system. The life of such patients is maintained only in ideal sterile conditions, any infection can lead to death. The scientists took the immune cells of such a patient and with the help of recombinant viral particles introduced the missing gene into them, which ensured the expression of the missing enzyme adenosine deaminase in the cells of the immune system. Then these cells were injected back into the patient, which ensured his full recovery. This success spurred researchers to new research, followed by a boom in clinical trials of gene therapy drugs.

This path in 20 years was long and difficult, full of successes and defeats. One of the early studies using adenoviruses resulted in the loss of a patient due to severe side effects. This case somewhat slowed down the development of gene therapy, but, fortunately, did not stop it. In 2012, the first registered gene therapy drug based on recombinant adenoassociated virus (AAV) GLYBERA appeared for the treatment of a rare incurable hereditary disease associated with lipoprotein lipase deficiency (LPL).

In 2016, the gene therapy drug STRIMVELIS was approved in Europe for the treatment of severe combined immunodeficiency associated with deficiency of the enzyme adenosine deaminase (ADA-SCID). In 2017, LUXURNA was registered, the first AAV-based drug for gene therapy of hereditary retinal dystrophy. In the same year, the first gene therapy drugs based on modified human T cells (CAR-T therapy) for the treatment of hematological diseases (acute lymphoblastic leukemia, B-cell lymphoma) Kymriah and Yeskarta were approved.

In May 2019, the FDA approved Novartis' gene therapy drug Zolgensma, intended for the treatment of children with spinal muscular atrophy (SMA).

In the coming years, it is expected to register a number of more gene therapy drugs for the treatment of incurable diseases, including in Russia. BIOCAD, one of the largest international innovative biotechnological companies in Russia, is also working on the creation of innovative gene therapy drugs.

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