Gene by appointment: will medicine be able to learn how to correct DNA errors
Gene therapy allows you to directly affect the genetic cause of the disease by delivering a working copy of the desired gene to the cells. For example, researchers in China have managed to reduce the level of "bad" cholesterol in a patient with a severe hereditary disease. How the technology works, what diseases it already helps to treat, and how widely it can be used in the future — in the Izvestia article.
How Gene therapy works
Gene therapy is changing the very principle of treating a number of diseases. Instead of constantly compensating for the consequences of a genetic defect, scientists are trying to deliver a working copy of the desired gene to the cells. For this purpose, viral vectors are used, which are peculiar transport systems capable of transferring genetic material directly into cells.
Anton Kiselyov, PhD, Head of the Laboratory of Molecular Genetics and Gene Therapy at the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, explains that the choice of viruses as such vectors depends on their natural ability to penetrate cells.
— When creating a therapeutic vector, the regions responsible for pathogenicity and reproduction are removed from the viral genome, and the necessary gene is placed instead. After being introduced into the body, the vector binds to receptors on the surface of target cells, penetrates into the cell and delivers therapeutic DNA or RNA," says Kiselyov.
The accuracy of hitting the right cells is very important here. It can be provided by the natural tropism of the virus, its ability to predominantly affect certain types of cells, or by changing the viral envelope. This allows you to control the spectrum of target cells.
This is exactly the principle used by the authors of the study, codenamed NGGT006. To treat homozygous familial hypercholesterolemia, a rare hereditary disease in which the body cannot remove "bad" cholesterol from the blood due to gene failures, they chose the adeno—associated virus (AAV), which has a high ability to penetrate liver cells. An optimized copy of the LDLR gene responsible for cholesterol was placed inside the vector. He must deliver it to the liver cells and thereby restore the mechanism of LDL elimination.
Mikhail Sokolov, Professor of the Department of Genetics at Moscow State University, Doctor of Biological Sciences, notes that the AAV virus used today is one of the most common platforms for creating gene therapy drugs. Unlike the original viruses, therapeutic vectors lack the genes necessary for reproduction and are not intended to spread infection.
"In the described case, the choice of AAV8 is precisely related to its pronounced ability to penetrate liver cells,— Sokolov explains.
An additional safety factor is that the adeno-associated viruses used do not integrate into the genome of the host cell. However, the technology cannot yet be called completely safe: the body can react to the viral vector, and the long-term effects of treatment require further study. Therefore, before the start of clinical trials, such drugs undergo large-scale preclinical studies on various animal models.
In the NGGT006 study, such tests were performed on mice and hamsters with the missing LDLR gene. The therapy reduced LDL levels, and in mice it also reduced the size of atherosclerotic plaques in the aorta. In Rhesus monkeys, a temporary increase in liver enzymes was observed after administration of the drug, but no serious side effects were detected.
Then the drug was tested for the first time on three patients with homozygous familial hypercholesterolemia. They were given different doses of NGGT006 and monitored for safety and LDL levels for 52 weeks. Liver enzymes increased in all participants, but this effect was stopped. In the patient who received the maximum dose, the level of "bad" cholesterol decreased from 11 mmol / l to less than 1.8 mmol / l three weeks after administration.
This technology demonstrates the principle on which modern gene therapy is based. The viral vector is used as a means of delivering genetic material, and the therapy itself is aimed at restoring impaired cell function.
Where Gene Therapy can Change Medicine
Today, rare hereditary diseases based on a single gene mutation remain the most promising area for gene therapy. According to Anton Kiselyov, in such cases, the delivery of his working copy or the correction of the damaged area allows you to directly influence the mechanism of the disease.
"This class includes, for example, spinal muscular atrophy (SMA) and Duchenne myodystrophy, and for some of these diseases, gene therapy has already entered clinical practice," the expert explains.
The experience of using adeno-associated viral vectors shows that this approach is already yielding results in a number of hereditary diseases. As Mikhail Sokolov notes, gene therapy developments have demonstrated effectiveness in SMA, hemophilia B and some hereditary diseases of the retina.
The example of the CMA is particularly illustrative. The disease is caused by mutations in the SMN1 gene, which is necessary for the functioning of motor neurons. The delivery of its functional copy makes it possible to restore the production of the necessary protein and affect the mechanism of the disease itself. This is one of the main advantages of gene therapy — the ability to work directly with the root cause of the disease.
The next stage is the use of genetic technologies against more common diseases. In oncology, such a transition has already partially taken place: one of the most famous examples is CAR—T therapy, in which the patient's immune cells are genetically modified so that they recognize and destroy tumor cells.
"Many people have probably heard, for example, about the success of CAR-T-cell therapy for the treatment of a number of blood cancers, which has proven to be very effective," says Sokolov.
Why can't gene therapy always be used?
However, it is much more difficult to transfer this experience to most mass diseases. If it is enough to affect one damaged gene in a monogenic disease, then the development of hypertension, atherosclerosis, or many types of cancer is determined by a combination of many genetic factors, lifestyle, and environmental influences.
This limitation is especially important to consider in relation to cardiovascular diseases. According to Kiselyov, research on gene therapy in this area is actively underway, but most approaches are still under development.
At the same time, certain diseases can already become the entry point of gene therapy into cardiology. A geneticist, researcher at the Scientific Advisory Department of the N.P. Bochkov Medical and Genetic Research Center, Candidate of Medical Sciences Peter Vasiliev notes that developments for the treatment of familial hypercholesterolemia are actively discussed at international scientific congresses. They have the greatest potential for patients with a severe homozygous form of the disease, in whom standard lipid-lowering therapy does not always achieve the desired effect.
"It seems to me that it is somewhat premature to consider gene therapy in relation to the classical, heterozygous form of familial hypercholesterolemia, especially as the first choice," Vasiliev notes.
There are already proven effective and safe treatments for this form of the disease, including statins, ezetimibe, antibodies, and PCSK9 RNA inhibitors. Therefore, according to the expert, the main importance of new gene therapy approaches today lies in the possibility of changing the treatment of the most severe forms of familial hypercholesterolemia.
In the future, the scope of the technology may expand as the delivery of genetic material and genome editing methods improve.
"The range of diseases for which gene therapy approaches can be used in clinical practice is expected to expand," says Kiselyov.
What challenges are there
Even if gene therapy shows convincing results in the first studies, this does not mean that it can be quickly made a standard treatment method. There are several barriers between an experimental drug and mass clinical practice, from the need to prove long—term safety to the creation of a complex production and medical infrastructure.
One of the main questions is related to how long the effect of treatment lasts. Anton Kiselyov notes that long-term observations are not enough for many gene therapy approaches. Therefore, scientists have yet to establish how stable the result is and what long-term consequences the intervention may have.
Mikhail Skoblov draws attention to the experience of previous developments. During the several decades of the existence of gene therapy, some clinical trials had to be stopped due to high toxicity, severe immune reactions, or the gradual disappearance of the therapeutic effect.
— The introduction of such technologies is very slow, precisely to reduce all possible risks. We need to conduct a large number of different experiments to verify the effectiveness and biosafety of such drugs, and this requires a lot of time and serious funding," says the expert.
High safety requirements are directly reflected in the cost of treatment. The development of a gene therapy drug requires sophisticated manufacturing technologies, specialized equipment, and a large amount of preclinical and clinical research. In addition, the use of such drugs often requires an individual selection of therapy and subsequent long-term monitoring of the patient.
Therefore, the availability of gene therapy depends not only on how successfully scientists have learned how to treat a particular disease. An entire system is needed capable of developing, manufacturing, registering and applying the drug. Kiselyov believes that for this, Russia needs to simultaneously develop a scientific base, its own production of viral vectors and reagents, specialized medical centers and the infrastructure of clinical research.
Timely diagnosis remains a separate problem. Even the appearance of an effective drug will not help the patient if the disease cannot be recognized and confirmed on a molecular level in time. According to Skoblov, the Russian medical and genetic service is already actively developing this area. The country has introduced neonatal screening for 38 hereditary and congenital diseases.
— However, this is not enough yet. The number of diseases that can be detected in this way is significantly less than the total number of known hereditary pathologies. That is why any research aimed at creating new drugs is of great interest and is actively supported in the field of medical genetics," Skoblov notes.
Economic support is also needed to expand accessibility. According to Kiselyov, the state will have to participate not only in financing scientific research, but also in creating mechanisms for reimbursing the cost of expensive therapy for patients. At the same time, it is important to improve the rules for registration of innovative drugs and the system of long-term monitoring of people who have undergone gene therapy.
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