Binary drug for gene therapy
Pills with double benefits
Marina Muravyeva, STRF.ruA group of scientists led by Professor Ancha Baranova (Laboratory of Genetic Epidemiology of the Medical and Genetic Research Center of the Russian Academy of Medical Sciences) is developing new ways of delivering genetic information to target cells for the treatment of socially significant diseases.
With a new vectorSeveral hundred projects in the world are devoted to the treatment of diseases with the help of genes (gene therapy).
They are based on the replacement of a defective gene in the patient's genome with an intact one. However, in many diseases, it is not necessary to introduce something new into the body, it is enough to suppress the work of individual genes (for example, in the fight against hepatitis C viruses, AIDS, etc.). About 10 years ago it was found that the expression of unwanted genes is suppressed using miRNAs that are similar in structure to a certain part of the gene and when interaction with large RNA can destroy it. This idea, attractive for therapeutic purposes, was seized upon by many scientists and attempts were made to develop a new generation of gene therapy drugs based on miRNA. Although the time of occurrence of this therapy is much younger than the gene therapy, it is closer to "going to the clinic," says Ancha Baranova. However, there are some difficulties.
DNA is a very stable polymer, scientists isolate it even from the bones of Neanderthals, mammoths (see "The Gene Hunter" for more details – STRF.ru ). RNA is very easily destroyed: its life in the blood lasts less than a minute. Therefore, a delivery vector is needed for miRNA. Until now, the choice has been limited to either viral or liposomal vectors. But everyone has disadvantages. Liposomes do not live long and deliver "gene drugs" mainly to the liver. And it's not safe to work with viruses. There is a great risk of damaging something in the genome, in particular, such "treatment" can lead to the development of cancer. This is a serious side effect of viral therapy.
"We have created a fundamentally new delivery vector that other laboratories can adopt," says Ancha Baranova. – This is another path on which you can go, achieve results. The basis of the new vector is DNA. But if earlier it was considered as something that needs to be delivered to cells, then here it is a kind of basket inside which a certain amount of miRNA is put and sent to cells."
Speaking about the originality of the development, Ancha Baranova explains that "ideas are carried in the air, but in an unformed form." Analysis of the scientific literature has shown that there were no proposals for a vector from pure DNA before. Only recently, scientists came across an article describing a new vector for miRNA delivery. It uses a whole set of components, including DNA. "I think the authors' working component is DNA, but they just don't know about it," suggests Ancha Baranova. – Judging by our calculations, most likely, DNA does the main work, and everything else is simply hung on it."
About the projectThis idea – to make a vector from DNA – appeared in Ancha Baranova two years ago.
At first, her American student at George Mason University worked on it (Professor Baranova's second job). But they were able to significantly advance this idea in Russia thanks to the financial support that the project received under the Federal Target Program "Research and Development in priority areas of Science and Technology for 2007-2012" (2009-2010).
Scientists Mikhail Skoblov (left) and Andrey Marakhonov (right) have developed DNA modification tools and have shown on a specially created model that the system works. Two Russian patents have been filed.
"It was a search job – very difficult and time–consuming," says Mikhail Skoblov, a leading researcher at the laboratory. – I had to put a large number of controls. Most of the work, probably 99 percent, went “into the sink.” After going through different implementation options, we tried to figure out what works and what doesn't. First of all, it was necessary to select a target that would suppress the expression of a certain gene. When they coped with this, they began to study how effectively it works on cell cultures. Various instruments were used to evaluate how this target penetrates into cells. The assembly of DNA baskets that protect the target is a separate big “song". They had to be modified so that they purposefully went to the right cells. This is a search of various parameters. Of course, some things are known from literature. But we tried to create a unique combination that works effectively."
The immediate goal of scientists is to ensure that this delivery system works efficiently and stably. While there are errors: the experiment goes better, then it gets worse. The system has many parameters that need to be investigated and their optimal combination selected.
Recently, scientists have submitted another application for participation in the Federal Target Program "Research and Development" in order to continue the project they started. In the future, it will be necessary to conduct experiments on model organisms – mice, rats. In addition, it is planned to continue research with the laboratory of the MGNC of the Russian Academy of Medical Sciences Natalia Veiko. She works with extracellular DNA, has already discovered an interesting phenomenon: oxidized DNA in some cells, primarily tumor cells, can cause apoptosis. This means that it is possible to make a "binary preparation", where both the delivered miRNA and the basket surrounding it have a therapeutic effect. So far, this is just an idea. Additional experiments can lead to significant results.
About prospectsThe system being developed by MGNC scientists in the future can be used to treat cancer, viral diseases (primarily those against which there are no vaccines – hepatitis C, AIDS), Parkinson's and Alzheimer's diseases.
In Alzheimer's, amyloid protein is deposited, which leads to the formation of plaques. If this protein were produced in smaller quantities, there would be fewer plaques or they would not appear at all. And then the disease developed in the patient, say, not in 80, but in 100 years.
In practice, medicines in the form of capsules have been used for a long time: inside they have an active substance, and the shell is pressed gelatin, which does not have any therapeutic effect, but only relieves the patient from unpleasant taste sensations while taking the drug. If a new DNA-based delivery vector is used, both the packaging and the filling will have therapeutic properties.
Of course, in order for all this to reach the consumer, dozens and hundreds of laboratories should join the research, and all over the world. Scientists of the Medical-Genetic Center have made the first step in this direction so far. The project lasted a little over a year. This is very small by scientific standards.
"I think miRNA–based therapy will eventually become available, and we are talking about either injections or transdermal delivery methods," says Ancha Baranova. – Viral vectors will never be cheap. The virus can be obtained in large quantities, but you need to check it for security. The liposome can be made cheap, but it has its flaws, and this vector is based on chemicals that are foreign. And here we can make these vectors from human DNA, including each individual patient. It's attractive. In addition, the use of DNA has already been approved by the Ministry of Health and Social Development."
About returning to RussiaAncha Baranova has been living and working in America for 8 years.
She comes to Russia several times a year, where she oversees the work of her laboratory at the MGNC RAMS. She considers the idea of the Russian government to attract scientists who have left to the country reasonable. But at the same time, she did not participate in the megagrant competition herself: "First of all, the strict requirements of the project are unacceptable to me – to be in Russia for four months a year. I participated in a smaller competition for a grant from the Institute of Genetics as a visiting specialist. Then it was necessary to spend two months in the country – this is more realistic. If there is such a request from the government to attract scientists from abroad to work with Russian specialists, then I am already working. And it is impractical to lure a scientist here to a permanent position. The most important thing is to establish integration. In the world, globalization is happening."
Those of our scientists who got into graduate school in the USA and then stayed there to work, should not be considered Russian. They just know how to speak Russian. It's the same as if an American scientist learns Russian in a course. If a person has lost integration with the Russian system, it will be as difficult for him to integrate back as for any foreigner. If they got an education here, immediately developed some scientific directions and integrated them, then, despite the fact that they left, they still remained Russian scientists. There are a minority of such people. Those who went to graduate school and postdocs are ordinary American scientists.
Professor Baranova considers her position more advantageous: she has the opportunity to apply for grants in two completely different systems – in Russia and the USA, to carry out joint projects, research. By the way, there is a widespread opinion that in Russia it is very difficult to fill out application forms, win grants, write reports – allegedly the process is very bureaucratic. Ancha does not fully agree with this. There are also many problems of about the same nature in the USA: "It seems to me that the Russian system is developing like a tracing paper of the American one. In the USA, they will come up with something crazy, our people immediately act similarly. In addition, in America, the grant cycle takes 10-12 months – from the submission of an application to the announcement of the results of the competition, and funding comes even later, often with a delay of a year, after all the formalities with permits have been observed. In Russia, the grant cycle takes a month. It's very attractive. The probability of winning a grant (competition) in both countries is about 10 percent, that is, to win one grant, you need to write 10 complicated bureaucratic applications. So don't complain. I don't think the Russian grant system is much worse than the foreign one."
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14.12.2010