The first swallow of gene therapy
The first genetic, allowed
In the EU for the first time it is allowed to use the drug,
designed for gene therapyAlexander Ryzhkov, "Newspaper.
Alipogene tiparvovec genetically regulates the level of fats in the blood, curing pancreatitis and preventing early heart attacks and strokes. Doctors hope that this is just the beginning of the era of gene therapy, which will bring the treatment of people to a fundamentally new level.
The drug alipogene tiparvovec was developed for the treatment of a rare hereditary pathology – lipoprotein lipase deficiency (also called hyperlipoproteinemia type I). With the insufficiency of this enzyme, the level of chylomicrons (particles involved in the transportation of fats) in the blood sharply increases. In patients, due to the fact that the vessels are "clogged with fat," a myocardial infarction or stroke can occur at the age of 20-25 years.
Among the less frightening consequences is spontaneous or caused by a violation of the diet, inflammation of the pancreas – pancreatitis. Alipogene tiparvovec alters the gene encoding the production of lipoprotein lipase.
In fact, the drug is a normal lipoprotein lipase gene "packaged" in the DNA of the viral vector (a particle that is used to deliver genetic material to target cells). In this case, the viral vector is an adeno-associated virus. This virus is absolutely harmless to the body (in any case, there is no evidence yet in favor of its pathogenicity), unlike, for example, retroviruses, which can also be used as viral vectors, but they can cause mutations and provoke the formation of tumors with a certain probability.
However, adenoassociated viruses also have disadvantages: the capacity of their genome is extremely low, that is, if it is necessary to "transfer" a sufficiently large gene with the help of a viral vector, it simply "will not fit" into it. Anyway, now a lot of drugs based on adenoassociated viral vectors are undergoing clinical trials.
In this case, another advantage of the selected adeno–associated virus is its affinity for muscle cells. Muscle tissue is the main supplier of lipoprotein lipase, and therapy is designed for a single intramuscular injection of the drug.
Alipogene tiparvovec has been tested in three clinical trials conducted in Canada and the Netherlands. The tests were conducted on 27 patients with hereditary lipoprotein lipase deficiency. All those who received the drug tolerated it well and between the third and twelfth weeks after administration of the drug showed a noticeable decrease in the concentration of fats in the blood. It is important to note that a single administration of the drug gives a persistent long-lasting effect and reduces the frequency of attacks of acute pancreatitis associated with a violation of fat metabolism. Plus, the use of this drug will allow patients with hereditary lipoprotein lipase deficiency to eat normally, without limiting themselves to foods rich in fats.
Article by Gaudet et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPL S447X) gene therapy for lipoprotein lipase deficiency: an open-label trial published on the website of the Gene Therapy journal June 21, 2012 – WM.
The registration of Alipogene tiparvovec is a turning point in actually opening a new field of medicine. Gene therapy has appeared relatively recently, but is developing very rapidly. The prerequisites for the emergence of the idea of gene therapy were discoveries in the field of biology and genetics. In particular, understanding the mechanisms of transformation of animal cells by tumor-forming viruses gave the impetus that was needed to develop a fundamentally new type of treatment. The concept of gene therapy originated in 1972, when the journal Science published an article by Friedman and Roblin "Gene therapy for human genetic diseases?". Already in the 1980s, methods of transferring genetic material from one animal to another were actively used.
The pioneer in the use of gene therapy in practice was the American physician William French Anderson, whose patient was a four-year-old girl named Ashanti de Silva, who suffered from hereditary adenosine deaminase deficiency. This enzyme in cells destroys substances that are toxic to leukocytes – white blood cells responsible for immunity. Thus, children with a deficiency of this enzyme have congenital immunodeficiency and are constantly ill, since their white blood cells are helpless against toxins. Anderson and his colleagues took the girl's blood, filtered out the leukocytes and "infected" with a virus that changed the DNA structure of these cells, whereby the missing enzyme began to form in them. These cells were injected back into the girl's blood. Constant improvements were observed during treatment, and over time the frequency of administration of the drug and the dose were reduced. However, there was no complete cure.
In 1992, Italian doctor Claudio Bordignon from the Vita-Salute San Raffaele University in Milan used hematopoietic stem cells (i.e. blood cell precursors) as vectors for gene delivery. In the future, this work was reflected in the first successful cure of the same adenosine deaminase deficiency in 2002. However, there were also failures.
In 1999, 18-year-old volunteer Jess Gelsinger died as a result of experimental treatment. He had a pronounced immune response to the introduction of the viral vector. And in 2002, the possibility of using gene therapy for adenosine deaminase deficiency was generally questioned when in Paris, children receiving gene therapy developed conditions similar to leukemia. Many clinical trials in the USA were suspended by the FDA (the Agency for the Control of Medicines and Food of the US government), it was necessary to reassess the ethical aspects of gene therapy.
Since the beginning of the XXI century, research in the field of gene therapy has continued. In 2003, a group of scientists from the University of California at Los Angeles managed to transfer genetic material to brain cells by overcoming the blood-brain barrier protecting the brain with the help of liposomes. Liposomes are bubbles formed from a double layer of special molecules – phospholipids. Inside these bubbles, you can put a medicinal substance that needs to be delivered to certain cells. The main useful property of liposomes in this case is their ability to penetrate through natural cell membranes. This scientific achievement has opened up prospects in the treatment of Parkinson's disease or Huntington's chorea.
In 2006, scientists from the Cancer Research Center of the US National Institutes of Health (Bethesda, Maryland) successfully cured metastatic melanoma in two patients by changing the genetic material of T-lymphocytes and thereby forcing them to attack cancer cells.
The development of gene therapy was still hampered by the problem of immune rejection of cells with altered genetic material. The solution to this problem was found by a group of scientists led by Dr. Luigi Naldini and Dr. Brian Brown from the San Raffaele Institute of Gene Therapy in Milan in May 2006. They suggested that the recognition of a new gene by immune cells can be "turned off". In experiments on mice, they used a special micro-RNA that changed a separate section of the DNA of immune cells in such a way that they stopped identifying and destroying genetically new cells.
Since then, the progress of gene therapy (at the level of scientific research) has been increasing: scientists have published works on the treatment of hereditary diseases with its help, were able to endow monkeys with color vision, proposed methods for the treatment of color blindness in humans, cured beta-thalassemia.
Now the first "genetic medicine" has been approved for use, and it can be assumed that in the future, interventions in the genome will allow treating more common diseases, predisposition to which is inherited.
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