- Dmitry Vladimirovich, recently scientists from the USA and Ireland have developed a hydrogel based on hyaluronic acid with nanoparticles containing microRNA. The hydrogel is injected into the tumor area, and it slowly releases microRNA, which inhibits tumor growth. How promising is this area of research?
- We are talking about one of the ways to deliver specific microRNAs to the focus of pathology, where they are gradually released from the hydrogel and begin to inactivate the oncogenes involved in the process. But the article states that this is a combination therapy using chemotherapy drugs. I note that the life expectancy of experimental mice increased from 24 days to only 32 - not a very impressive result. In addition, the long-term consequences of such therapy are still unknown. It is known, for example, that the same microRNAs can function as oncogenes in some types of tumors and as suppressors in others.
Given that osteosarcoma is a highly aggressive bone cancer that mainly affects children and adolescents, from my point of view, it may be better to perform an amputation, replacing the limb with a bionic prosthesis, than to risk experimental treatments.
—If DNA and coding RNAs have been known for a very long time, then microRNAs were discovered only in 1993. Please tell us what this part of the genetic mechanism is, what functions does it perform in the body?
- MicroRNA genes are an integral part of the genome, as are protein-coding genes. The human genome contains about 24,5 genes encoding various proteins, and at least <>,<> genes encoding microRNAs.
MicroRNAs consist of 19-25 nucleotides - this configuration is processed. - RT) from short chains of 70-100 nucleotides. MicroRNAs are very conserved, although mutations are possible. Their main function is to suppress the translation of messenger RNA, that is, to block the synthesis of proteins. This phenomenon is called RNA interference, its discovery was awarded the Nobel Prize in 2006.
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Each microRNA is able to regulate the work of at least 200 genes. Many genes have binding sites (regions of a macromolecule that specifically bind to other molecules) for several different microRNAs. In general, microRNAs regulate the work of at least 30% of genes. RNA interference is an integral part of the epigenetic regulation of gene expression. MicroRNAs are involved in all cellular processes, including DNA methylation (epigenetic regulation of the genome. - RT), functional modifications of proteins and protein complexes.
- The information encoding microRNA is contained in a part of DNA that was previously considered something like useless ballast. It turns out that the peculiarities of microRNA are inherited? To what extent has this process been studied, are there any, for example, genetic diseases associated with microRNA?
- Yes, it was previously believed that the bulk of the genome, which does not code for proteins, is ballast. But there is nothing meaningless in nature, we just don't know a lot. Man conquers space, studies the depths of the sea, but at the same time we know very little about our biology, the functioning of the genome and epigenome, interactions at the level of DNA, RNA, proteins - about everything that today science collectively calls omics regulation of the body.
The process of RNA interference and its nuances have been studied very well to date, but scientists are constantly looking for new microRNAs, as well as exploring the functional relationships of microRNAs with DNA, coding and non-coding RNAs, as well as protein complexes.
As I mentioned above, microRNAs are evolutionarily very conserved, so the hereditary transmission of this part of the genome is not in doubt. With the exception of some individual mutations, in general, the peculiarities of microRNAs are transmitted from generation to generation.
As for diseases, microRNAs are not directly related to them, but at the same time they are indispensable participants in various pathological processes, such as oncological, neurological and neuropsychiatric, autoimmune, endocrine, etc.
What are the differences between microRNAs and other non-coding RNAs in their functions and mechanism of action?
- MicroRNAs are the simplest class of non-coding RNAs, they are small in size and, accordingly, in function. There are still a myriad of small, medium, long non-coding RNAs that perform their functions at different stages of the development of the organism and in different conditions.
Transfer RNA derivatives (tsRNAs) are formed under various stressful conditions. They are involved in a variety of molecular processes, such as RNA modification, gene regulation, protein synthesis, as well as in the regulation of cell division and stress response. Their abnormal expression is found in various diseases, such as pathological disorders as a result of stress, numerous types of cancer, viral infection and neurodegenerative diseases. The heterogeneity and stability of tsRNA allow them to be good biomarkers for the diagnosis and prognosis of cancer and other diseases such as osteoarthritis, osteoporosis, Parkinson's disease, Alzheimer's, multiple sclerosis.
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Circular RNAs were first discovered in 1979, but then scientists were of little interest. And recently it was discovered that cRNAs can, like sponges, hold microRNAs in themselves, blocking their activity. Also, circular RNAs are able to translate (convert. - RT) into short protein molecules, peptides, and in addition, act on DNA - regulate the work of some genes.
Circular RNAs are especially abundant in the brain, they circulate freely in the blood plasma. The presence and amount of some circular RNAs in blood plasma can also be used as biomarkers for diagnosing and staging some diseases, including cancer.
Long non-coding RNAs (lncRNAs), of which there are already more than protein-coding genes,have greater cellularspecificity than proteins and act as regulatory elements in many complex processes, including cell growth and differentiation. – RT), apoptosis, stem cell reprogramming, cell cycle control, heat shock response, as well as maintaining the integrity of the cell structure. In addition, they are able to regulate the synthesis and degradation of messenger RNAs, which ensure the functioning of the genome. They are very valuable biomarkers of various pathological processes.
— What types of microRNA-based drugs are already available in the world and in Russia? What diseases do they treat and how effective is it compared to traditional therapy?
- So far, there is not a single registered drug based on microRNA in the world, although research is actively underway. Now a number of such drugs are being developed abroad. For example, there are two developments aimed at treating hepatitis C - Miravirsen and RG-101. Both drugs are modified RNA molecules capable of blocking miR-122 microRNA in the human liver, which is necessary for the hepatitis virus to replicate. The developments have shown good efficacy, Miravirsen even passed the second phase of clinical trials. But work on RG-101 has been suspended due to a number of serious side effects.
MicroRNA-based drugs have also been developed for the treatment of non-alcoholic steatohepatitis (liver damage associated with fatty degeneration, fibrosis and inflammation - RT) and cholestatic diseases, but these studies have also been suspended.
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In fibrotic diseases in the body, the synthesis of microRNAs of the miR-29 family decreases, which normally block the excessive accumulation of connective tissues. The level of miR-29 can be restored with the drug Remlarsen (MRG-201), which is also currently undergoing clinical trials. A similar approach in the future can be applied in the treatment of oncology. For example, Mesomir is able to replace miR-16 microRNA, the synthesis of which in the body is suppressed in various types of cancer.
MicroRNA miR-92 prevents the formation of new vessels in tissues, and MRG-110 will be able to stop its production in the future. This will help cure ischemic conditions such as heart failure. This drug has not yet received registration and is undergoing clinical trials. MicroRNA-based drugs are also being developed for the treatment of Crohn's disease and ulcerative colitis.
Russia is also working in this direction. The Laboratory of Molecular Genetics of Complex Inherited Diseases of the Research Centre for Medical Genetics has already developed a new drug for the treatment of colon cancer based on small interfering RNAs. Preclinical studies have demonstrated its high efficacy and low toxicity, immunogenicity and mutagenicity.
— What are the main difficulties that arise when creating microRNA drugs? For example, is it true that artificially synthesized microRNAs are destroyed in the cell by enzymes? Have scientists managed to solve this problem?
- In fact, small RNAs are much more stable than messenger RNA. Synthetic oligonucleotides are used in microRNA preparations, they can withstand room temperature and can persist in the body for a long time. However, there are difficulties with the targeted delivery of such compounds to the pathological focus. Nucleic acid-based therapeutics do not penetrate the cell membrane well. Different approaches are used to transport such compounds within the body: using nanoscale carriers, viral transduction (transfer of genetic material from cell to cell using viruses. — RT), etc.
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- Can microRNAs be used to diagnose or predict diseases? Are there such tests in medical practice?
— Yes, such diagnostic and prognostic systems already exist, and not only on the basis of microRNAs, but also on other non-coding RNAs. Data on RNA circulating in the blood or other biological substances of the body make it possible to diagnose various types of malignant tumors. So, there are special panels for detecting primary cancer of unknown origin, for detecting thyroid cancer. Clinical trials are underway diagnostic system based on the analysis of microRNAs for the early detection of Alzheimer's disease, etc. Not all of the diagnostic systems being developed have been certified, but some tools are already at the disposal of doctors.