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Obese prognosis: scientists create "smart" cells against cancer and obesity
Russian scientists are working on a fundamentally new approach to cell therapy. They create two types of "smart" cells: to fight cancer and to treat obesity. Instead of constantly editing the genome, they plan to temporarily "silence" unnecessary genes using epigenetic modifiers, leaving the hereditary code intact. This makes them safe and suitable for mass use. For more information, see the Izvestia article.
How smart cells work
Scientists at Sirius University of Science and Technology are creating two types of "smart" cells: to fight cancer and to treat obesity. Both technologies are based on reversible epigenetic editing. Instead of constantly editing the genome, they plan to temporarily "silence" unnecessary genes using epigenetic modifiers, leaving the hereditary code intact.
According to scientists, today cell therapy is one of the most powerful tools in the fight against cancer. But it has serious limitations.: This is an expensive treatment method, and it also takes weeks to manufacture drugs and works only on the cells of the patient himself. In elderly or severely weakened people, these cells are often too few or they are no longer able to cope with the task.
Therefore, experts propose a fundamentally new approach — not to cut out sections of DNA, as is done in classical gene therapy, but to temporarily "silence" unnecessary genes. As a result, the molecules carrying the hereditary information will remain intact.
The project consists of two parts. The first is the creation of universal CAR-T cells to fight tumors. These are the "fighters" of the immune system, trained to destroy cancer. But the tumor is able to "drown them out" by turning on the brakes in them — the so-called immune checkpoints (PD-1, LAG-3 and others). To get around this, the authors of the project want to temporarily disable several such brakes at once using epigenetic modifiers. We are talking about the genes responsible for recognizing "us" and "others". By disabling them, it is possible to make CAR-T cells "invisible" to the patient's immune system. In this case, the process will become reversible: in case of an error, specialists will always have the opportunity to return to the initial stage in their work. This means that one drug will be effective for a large number of people at once. Without the risk of rejection and long waiting for the medicine.
Project Manager Egor Prokhorchuk
— The essence of the project is to minimize the immune response to foreign T cells. Using certain genetically modified approaches, we can reduce the expression of certain molecules on the surface of T cells, so that someone else's immune system either recognizes them worse or does not recognize them at all. Thus, the patient's immune response will be significantly less," Igor Deev, deputy head of the research group at the Scientific Center for Genetics and Life Sciences at Sirius University, told Izvestia.
The project is headed by Corresponding Member of the Russian Academy of Sciences, Doctor of Biological Sciences, Head of the Scientific Center for Genetics and Life Sciences at Sirius University Egor Prokhorchuk. The research is being implemented within the framework of the state program "Science" of the federal territory.
Cell therapy of obesity
The second part of the project is cell therapy of obesity. This disease often develops due to inflammatory processes that disrupt metabolism, accelerate aging, and make a person vulnerable to diabetes, heart attacks, and strokes. Modern pharmacological agents can help, but not everyone, the scientists said. In addition, their validity period is short-lived and requires the patient to constantly take appropriate medications.
Recently, experts have discovered a rare population of monocytes with the CD7 marker, which appear in humans and mice after losing weight and help maintain the result. These cells migrate into adipose tissue and trigger the process of thermogenesis — burning fat with the release of heat. The authors of the project want to create universal CD7 cells that can be injected into obese patients.
— Epigenetic genome editing is considered a safer alternative to DNA editing. However, its long—term effects and the specificity of its work require further in-depth research to ensure that there are no unforeseen consequences for patients," said Igor Deev.
Sirius scientists plan to receive not just a series of new drugs, but a whole platform for creating "smart" cellular drugs — ready-to-use, standardized, safe and affordable. This can change the rules of the game not only in oncology, but also in the treatment of metabolic diseases such as type II diabetes mellitus.
— Epigenetic editing is the future of medicine, because it is here that the mechanisms of cell rejuvenation, tissue regeneration, and treatment of many chronic diseases and cancers lie. The fact that such projects exist in the Russian Federation is very remarkable, such practice will allow us to develop the most advanced methods of therapy," Mikhail Bolkov, an employee of the Institute for the Study of Aging at the Russian State Scientific and Clinical Center of the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, commented on the development.
Sirius University's methodology is based on reversible epigenetic editing — it's like a light switch that can be flipped without changing the wiring in the house, explained molecular biologist Arina Kholkina. Such modifications are reversible chemical changes in DNA and histones that regulate the activity of genes without interfering with their sequence. Scientists do not rewrite the genome, but temporarily "mute" the work of the necessary sites, for example, using methyl groups.
—The safety of the method is ensured by the absence of direct chromosome breaks and random mutations typical of classical genomic editing," the expert noted.
The potential disadvantages of the platform are related to specificity: epigenetic effects depend on the context of the cell, inappropriate changes in gene regulation are also possible, and reversibility may be incomplete or uneven in different tissues, says Albert Rizvanov, head of the Personalized Medicine Center of Excellence at Kazan (Volga Region) Federal University. There may also be security issues. It is necessary to prove the stability of the specified labels when zooming, it is important to confirm the stability of the effect and the absence of pro-inflammatory consequences. And finally, there is a question from the regulator — the requirements for controlled epigenetic interventions are only being formed.
"Despite this, the platform looks promising because it allows you to fine—tune multiple targets without damaging DNA and, if necessary, cancel the effect," the expert concluded.
Now scientists are going to send the first cell line for in vivo experiments (on animal models) and will test it on mice, Igor Deev said.
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