18 January 2013

Gene therapy of infarction: latest news

A heart instead of a scar

Karen Shainyan, Radio LibertyGeneticists managed to reverse the course of events in myocardial infarction and grow a healthy heart muscle in place of the scar.

This usually happens like this: the blood vessel becomes clogged, and the part of the heart muscle that he fed dies. In ordinary life, a scar inevitably forms in place of dead muscle fibers, which does not contract, the heart pumps blood worse, and life-threatening heart failure develops. In ordinary life, a heart attack is irreversible, like many other biological processes. But now, in genetic laboratories, where things impossible in ordinary life have been happening for a long time, scientists have managed to start the reverse course of things and turn scar tissue cells into healthy working cardiomyocytes.

Strictly speaking, for the first time something like this was not done now. In 2012, Japanese geneticist Shinya Yamanaka received the Nobel Prize in Medicine and Physiology exactly for the fact that six years earlier, in 2006, with the help of genes, differentiated cells of an adult organism returned to the stage of young stem cells, from which, depending on the conditions, any tissue can develop.

Also last year, geneticists from California studied which genes work in healthy heart muscle cells, and by trial and error selected a minimum set of three genes (this cocktail they called GMT), with which scar tissue cells can be converted into cardiomyocytes. As a result, the heart of mice who were injected with this cocktail after an artificial heart attack worked in many ways better than in mice from the control group. The results were published in May 2012 in the journal Nature. (For a brief retelling of the work, see the note "Gene therapy for the treatment of heart attack" – VM.)

In the January issue of the Journal of American Heart Association, an article was published by other American geneticists, this time from the East Coast, from Cornell University Medical College, who developed the idea and added one ingredient to the GMT cocktail that significantly enhances its effect. We are talking about the VEGF gene, which causes blood vessels to grow (the so-called endothelial growth factor). And first they injected mice with this same vascular growth factor, and three weeks later – the already well-known cocktail of the other three genes (GMT). Thanks to an additional component, the whole gene-therapeutic cocktail turned out to be four times more efficient: the hearts of animals that were first injected with VEGF and then GMT worked four times better than those of mice that got only GMT, and eight times better than those of mice from the control group who were injected with simply "meaningless" DNA. The activity of the mice's heart was assessed by the ejection fraction, a standard indicator used in cardiology.

After reading the press release on the Cornell University website, I contacted Dr. Ronald Krystal, one of the authors of the study. I couldn't wait to find out the details of exactly how this transformation takes place. Cardiomyocytes and fibroblast from scar tissue are not much more similar to each other than a desk and a crow:

To make one out of the other seems to me not a biochemical, but an alchemical miracle. How is this possible and what exactly is going on in the cell?

"We don't know," Dr. Crystal calmly replied in a cheerful voice, although our conversation took place at six in the morning in New York. – Maybe fibroblasts return to the state of stem cells and then become muscle fibers, or it happens directly – these nuances are not known to science. I can assume that they return to more primitive stages of their development, and then differentiate into cardiomyocytes, but this is just a guess. We know that these genes play an important role in the early development of our heart, even before birth, when the heart is formed during intrauterine development."

Regardless of these biochemical nuances, the experiment turned out to be more than successful. The question is whether this gene cocktail will work as well on humans as on mice. By themselves, the genes that were used in the experiment are the same in both. "And in all people, regardless of their genotype and particular characteristics, these genes are also the same," said Dr. Crystal. – It is likely that there are other genes that affect this process, while we do not know it. These four factors that we used are responsible for the basic biological processes that work the same in all people. Perhaps those still unknown genes are different in you and me, but we won't know until we start human studies."

And here, of course, is the most unpleasant. According to Professor Krystal, we will have to wait for these tests for another five to ten years. As it often happens, it all comes down to security issues. Different carriers are used to deliver genes to the workplace, and in this experiment, Cornell geneticists used two types of viruses.

To deliver VEGF, an adenovirus was used, which is actually already being used in humans for gene therapy of a special form of pancreatitis (Glybera therapy). That is, the safety of working with adenoviruses has already been proven. The situation is much more complicated with the lentivirus, which scientists used in the second stage to deliver GMT genes into the cell. The lentivirus is embedded in the cell's own DNA and remains there as long as the cell itself lives. Adenoviruses are safer because they are not embedded in the DNA of the cell and, like a runny nose, disappear after two to three weeks.

"We used lentivirus on mice simply because it is more convenient,– says Dr. Crystal. – He is able to transfer more genes, and it is easier to work with him. Adenovirus is more difficult to use, but if we talk about experiments on humans, it is more expedient. We will probably use it on people."

"First of all, we should not forget that at least a third of drugs and methods that work on mice turn out to be ineffective when they are tried to be used on humans," Professor Sergey Kiselyov, head of the Laboratory of Genetic Foundations of Cellular Technologies at the Institute of General Genetics, told me. – Secondly, the authors do not work with the cause of a heart attack, but with the consequences. It would be safer to try to influence the genes that predispose to the development of a heart attack, but we do not know what these genes are, and no one knows."

However, it is possible to influence the cause of a heart attack right now, without waiting for big discoveries and human trials of what works on mice.

While human trials of gene therapy for heart attack have not begun, there are other ways to deal with the causes of heart attack, and they have long been known.

"You see, a heart attack is like a blockage in a pipe," Dr. Crystal told me at parting. – The vessels that feed the heart become clogged because we eat fatty meat instead of vegetables. Of course, heredity is also important, and there are hundreds of genes that affect predisposition to heart attack. However, we do not choose parents, but we choose a way of life. You can monitor your weight, eat healthy food, limit yourself in alcohol, do not smoke and do not use drugs. Drink aspirin or baby aspirin. For example, I take a pill every day and I advise my patients because it reduces the risk of a heart attack. Maybe if all people follow these rules, we won't need any gene therapy."

Portal "Eternal youth" http://vechnayamolodost.ru18.01.2013

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