All-Russian Multimedia Conference «Gene Therapy: Present and Future»
On December 14, 2022, the All-Russian multimedia conference «Gene Therapy: Present and Future» was held in Moscow, where leading experts discussed the prospects that the personalized approach in the fields of neurology, endocrinology, treatment as monogenic, and multi-factor diseases. A separate discussion focused on genomic editing as a promising approach to gene therapy.
The event was organized by the Association of medical geneticists with the support of the Research Centre for Medical Genetics.
The moderators of the plenary session were Sergey Kutsev, academician of the Russian academy of sciences, Director of RCMG, president of the Association of medical geneticists of Russia, chief external expert in medical genetics of the Ministry of Healthcare of Russia, and Svetlana Smirnikhina, the head of the genome editing laboratory at RCMG.
Gene therapy and early diagnostics
Sergey Kutsev, Director of the Research Centre for Medical Genetics, chief external expert in medical genetics of the Ministry of Healthcare of Russia, academician of the Russian academy of sciences, reported on the first results of the use of the drug onasemnogen abeparvovek by patients which were revealed by a pilot project on mass neonatal screening for spinal muscular atrophy. The Research Centre for Medical Genetics launched a pilot project in early 2022 in 8 regions of Russia. To date, 19 patients have been identified with spinal muscular atrophy in the pre-symptomatic stage.
“Twelve of these children have already received the gene replacement drug onasemnogen abeparvovek. Several children have been monitored for five months and the results show that their development is in line with their age. This is an amazing result”, - said Sergey Kutsev.
Sergey Illarioshkin, academician of the Russian academy of sciences, Deputy Director for scientific work of the Scientific Centre for Neurology, told about foreign observations of the use of the drug nusenersen for the treatment of spinal muscular atrophy type 1, which have been conducted for 1 year. They show high efficacy in therapy: the patient’s trouble-free survival rate rises from 30% to 70%.
“Before our eyes, gene therapy drugs are actually changing the traditional idea of dividing the AGR into different types and subtypes, changing forecasts of disease flow. For example, when prescribing treatment at the pre-symptomatic stage, the disease may not develop at all or manifest at a later date. When prescribed with a specific treatment in the early stage of AGR, the disease proceeds in a milder form, it can be said that there is a transformation of the phenotype AGR 1 to AGR 2 type. Studies show that if the drug is prescribed as early as possible, before the appearance of motor manifestations of the disease, you can achieve almost normal motor indicators of child development. So now there is a struggle for the earliest possible diagnostics”, - said Sergey Illarioshkin.
Gene therapy in neuroscience - transition to personalized medicine
Gene therapy allows to speak about personalized approach in treatment of neurological diseases. A vivid example of this is the story of a child from the United States who was diagnosed with neuronal ceremonial lipofuscinosis caused by a rare mutation. In the shortest possible time, an individual drug was developed based on antisense oligonucleotide. For 4 years of its use, doctors observed an improvement in the clinical picture.
“This is a striking example in the history of medicine, when such a drug was created for one patient. Unfortunately, the patient could not be rescued, but the experience raised a number of ethical, legal questions for both society and developers. The further the practice of developing such drugs will develop, the more questions will arise”, - said Sergey Illarioshkin.
Domestic gene therapy technologies are also developing today. A few years ago an innovative drug was created for the treatment of lateral amyotrophic sclerosis. It represents the design of recombinant pseudo-adenovirus particles that express the genes of vascular endothelium growth factor (VEGF) and human angiogenin (ANG). Studies have shown that the drug slowed the rate of neurological deficiency and respiratory disorders in patients. Production has been suspended for various reasons, but a new version is planned and a series of experiments on transgenic mice has already started.
“We have reached an agreement on the creation of an improved version of the drug on the same model with the prospect of implementation in the clinic. Gene therapy today is a number of new approaches that are being actively developed and, I hope, will be introduced into the clinic in the coming years, including with the participation of domestic developers. We are entering a new century of gene therapy and personalized neuroscience”, - Sergei Illarioshkin summarized.
Prospects of gene-cell therapy in the treatment of multi-factor diseases
Today in Russia there are 65 million inhabitants suffering from some kind of endocrine disease. Maria Vorontsova, leading researcher in the department of child nutrition and reproductive somatic development at NMRC for Endocrinology, the head of the molecular endocrinology laboratory at Moscow State University named after M.V. Lomonosov, a member of the Presidium of the Russian association for the promotion of science, stressed that all current gene therapy strategies are applied in the field of endocrinology. She elaborated on the treatment of type 1 diabetes mellitus, in particular on modern approaches to induction of insulin secretion and reduction of the risk of autoimmune response. CRISP Cas9 allows liver and intestinal cells, as well as pancreatic beta cells, to produce insulin.
“However, there are risks that these cells will be subjected to autoimmune aggression. In such cases, combined approaches using monoclonal antibodies to T-cell receptors lead to their inactivation. The effectiveness of therapy is increased to 80%, but so far it is shown on biological models”, - stressed Maria Vorontsova.
Also, in the treatment of diabetes mellitus, the use of mesenchymal stromal cells (MSC) is very promising, as they have immunomodulating properties. Animal studies have shown that the introduction of MSC helps to improve the survival and even regeneration of beta cells in the pancreas.
“It has been observed that the MSC-implanted cells near the Langerhans islet cells themselves began to differentiate into insulin-producing beta cells. They are also able to reduce immune response and protect beta cells from autoimmune aggression. In this connection, the study of the transplantation of beta cells grown in vitro, together with mesenchymal stromal cells, is gaining popularity”, - said Maria Vorontsova.
Sergey Kutsev noted that the developed gene-cell approaches open new opportunities in the treatment of multi-factor diseases.
Genome Editing: a Breakthrough 2022
About half of all CRISPR Cas9-based drugs currently in clinical trials are directed at cancer treatment. However, none has yet reached phase three. The drugs for the treatment of monogenic diseases that have passed the preclinical, today only three, but their clinical trials are at the final stage.
«The 2022 breakthrough is three phase III clinical trials of CRISPR Cas9-based drugs for the treatment of monogenic diseases, we are on the threshold of approval of the world’s first drug based on CRISPR Cas9», - said Svetlana Smirnikhina, the head of the genome editing laboratory at the Research Centre for Medical Genetics.
The preparation for the treatment of beta-thalassemia has reached the third phase: genomic editing can be used to stimulate the production of fetal haemoglobin, which will replace adult haemoglobin. There has already been an increase in the proportion of fetal haemoglobin in different patients, and this effect is long-term.
Genomically edited drugs for monogenic diseases such as sickle-cell anaemia, beta-thalassemia, haemophilia B, mucopolysaccharidosis I and II types, congenital Leber amavrosis 10, hereditary transthyritine amyloidosis, Duchen myodistrophia.
Genome editing for Duchenne muscle dystrophy in RCMG
The genome editing laboratory at RCMG proposed its own approach to treating Duchenne myodistrophia. It aims to correct a mutation in the DMD gene that causes a reading frame shift. The approach is to cut out 11 to 12 exons with CRISPR Cas9, so the synthesized protein is able to perform most of its functions. The first laboratory work and research of scientific literature showed the prospect of such an approach.
“The literature describes one exon deletion patient 11-12. The first signs of the disease began to be noticed at the age of twenty: it is weakness, rapid fatigue. The case is notable for the fact that the patient has no muscle manifestations of the disease, and cardiomyopathy has been identified. This tells us that Duchenne myodystrophy can take place in a lighter form, and our goal is to make the heavy phenotype of the disease more mild”, - said Olga Levchenko, the leading researcher of the genome editing laboratory at RCMG.
On the HEK 293T line, researchers searched for the best plasmid variants and then conducted experiments on the myoblasts of healthy donors. The results show that the technology is effective, with deletion at the DNA and RNA levels. Soon the researchers plan to move to work with the cells of patients with the corresponding mutation in the DMD gene, there are 21 of them in the database.
Video recordings for medical professionals will soon be available on the website https://genetherapy.significo.ru/
Material on the work of the conference "Gene Therapy: Present and Future" on the air of the "Vesti" channel Russia. Follow on 12:05 https://smotrim.ru/video/2530353