Russian scientists tested a new approach to fight viruses. They used genetic editing technology to trigger the defense mechanisms of cells that had already been infected by the infectious agent. By artificially activating the APOBEC/AID protein family, they managed to suppress the replication of hepatitis B and D viruses by 80–85%. Now specialists intend to identify the most universal intracellular factors and create the first broad-spectrum medicine based on them. According to experts, the new the method may be an effective treatment, but side effects must be carefully investigated.
Self-reliance
Specialists from the laboratory of genetic technologies in the creation of medicines at the Institute of Medical Parasitology, Tropical and Vector-Borne Diseases of Sechenov University have proposed a new method of combating infections. They discovered a number of proteins that suppress the activity of viral particles that have entered the cell. Scientists were able to randomly engage this mechanism using the CRISPR/Cas9 gene editing system. Now they intend to determine the most universal proteins effective against most viruses, and based on them create a medicine against a wide range of such diseases.
Today, the main means of combating viruses are vaccines and antibody-based drugs. They must prevent particles from penetrating into the cell.
But if this does happen and the person is already sick, then the only means of control may be interferon. This type of protein activates hundreds of antiviral genes, which allows replication to be stopped or slowed down. However, the substance is effective only against a few types of infection.
– We have developed an approach to identify and activate, using the CRISPR/Cas9 gene editing system, individual key antiviral factors that are independent of interferon but can block infections. This technology can be used to create a drug effective against a wide range of diseases,” said Dmitry Kostyushev, head of the laboratory.
Scientific team selected 157 genes and analyzed their response to hepatitis B and D pathogens. This made it possible to isolate a number of antiviral factors in cells.
It turned out that APOBEC/AID protein family, effective against DNA and RNA viruses. As experiments on cell models of chronic infections have shown, it was activation of just a few of these proteins is sufficient to suppress the disease by 80–85%. Analysis of the usefulness of this approach against a number of other severe cases showed similar results.
— Our the hypothesis that individual intracellular factors can effectively suppress viral replication was confirmed. The primary task now is analyze not individual genes, but entire groups on the widest possible set and select the most universal antiviral factors. They will be possible in the future used to combat not only existing infections, but also those that will appear in the future. Judging by the forecasts of the WHO and the Ministry of Health, pandemics will occur more and more often, so the arsenal of means to combat them needs to be expanded, said Dmitry Kostyushev.
Side effects
Antibodies and T cells that specifically respond to viral proteins are adaptive immunity that is developed after encountering a pathogen, Mikhail Boklov, a researcher at the Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, explained to Izvestia. In addition to it, there are also innate mechanisms, which include APOBEC/AID. They often do not allow the infection to run rampant and cope with it without triggering adaptive immunity. This is 90% of the body's defenses that work continuously.
— Scientists have discovered that APOBEC/AID proteins can destroy the virus right inside the cell.
They rewrite the code, changing one “letter” to another, without having a toxic effect. But Excessive activation of proteins leads to mutations in a person's own genome, including genes leading to cancer. Therapy may have side effects, including cancersaid Mikhail Bolkov.
According to him, a set of precise tools based on modified CRISPR-Cas9 systems, called CRISPRa, was developed to directly activate the desired genes. It has been shown that this approach is safe and effective, for example, in correcting genetic defects and suppressing HIV infection.
— This is a very relevant topic, because So far we do not have reliable drugs that cure hepatitis B and D. The available drugs only suppress the activity of these viruses. These studies are welcome, but so far they have achieved a reduction in replication by 80% and only in the experiment. A lot of work still needs to be done for such a medicine to come into practice,” said RAS academician and epidemiologist Vadim Pokrovksy.
Scientists propose to direct CRISPR/Cas9 sequences that trigger antiviral reactions into cells using a delivery system they previously developed based on biological nanoparticles.
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