Gene therapy has problems again
Difficulties on the path of gene therapy
Maxim Rousseau, Polit.roo
Massachusetts biotech company Bluebird bio has decided to stop clinical trials of a promising gene therapy for sickle cell anemia after two participants developed cancer similar to leukemia. The incident revives old concerns about the potential risks of gene therapy with viral gene carriers.
Currently, experts are trying to find out whether the virus that was used to deliver the therapeutic gene caused the cancer. There is also a possibility that the cancer arose as a result of chemotherapy, which patients received at the preliminary stage. "Whatever the reason, this is a really sad event," says Donald Cohn of the University of California, Los Angeles, who led the trials of gene therapy for sickle cell anemia and other diseases.
Bluebird bio was founded in 1992 by scientists from the Massachusetts Institute of Technology, originally it was called Genetix Pharmaceuticals. Since 2001, she has focused her efforts on creating genetic therapy for sickle cell anemia and beta-thalassemia, two of the most widespread severe human genetic diseases. In 2010, preliminary test results were published in the journal Nature, according to which a patient with beta-thalassemia did not need blood transfusions for 21 months after treatment. This was the first ever long-term correction of a major human genetic disease using gene therapy. In the fall of the same year, the company was renamed Bluebird bio. The company develops methods of gene therapy for hereditary diseases, as well as leukemias, lymphomas and other cancers. The biggest success of the company was the Zynteglo method for the treatment of beta-thalassemia using genetically modified blood stem cells of the patient. After successful trials, the method was approved by regulatory authorities in the USA in 2013 and in the European Union in 2019.
Sickle cell anemia is caused by a mutation in a gene encoding one of the subparticles of the hemoglobin molecule. It leads to a change in the shape of a protein molecule in red blood cells (instead of hemoglobin A, hemoglobin S appears). Erythrocytes with defective hemoglobin have a characteristic crescent shape, whereas normal erythrocytes have the shape of a disk with a concave core. Sickle-shaped red blood cells are destroyed more often than usual, which leads to permanent anemia, since due to the death of red blood cells, tissues do not receive oxygen. In addition, such red blood cells are less plastic and less able to pass through narrow capillaries.
Frequent blockage of capillaries in patients leads to various disorders, the appearance of thrombosis in the liver and spleen, arthritis, ulcers on the legs, besides they are always characterized by anemia and constant fatigue. In some cases, blockage of the retinal capillaries can lead to blindness. The only form of non-palliative treatment for such patients until recently was a donor bone marrow transplant, but not all of them manage to find a suitable donor, besides transplantation requires lifelong use of drugs that reduce immunity.
The method that Bluebird bio tested is that blood stem cells are taken from the patient. In the laboratory, they are infected with a specially modified virus from the genus of lentiviruses. The virus, which in this case is called a vector, carries a gene into the cells that will produce the right hemoglobin. After that, the cells are returned to the patient's body. Fourteen people who received the latest version of this therapy completely got rid of the symptoms of sickle cell anemia.
But now the news has come that a patient who participated in one of the trials five years ago has developed acute myeloid leukemia (AML). Another has myelodysplastic syndrome (MDS), which can develop into AML. In 2018, MDS was detected in another participant in the same trial, but then tests showed that it was probably the result of DNA damage during chemotherapy, which destroys the patient's blood cells to make room for the treated cells. Bluebird bio has decided to interrupt the current tests to understand the reasons.
Fears that the side effect of gene therapy may be the appearance of cancer have been expressed for a long time. And they are not groundless at all. If viruses are used to deliver a therapeutic gene to the patient's cells, then theoretically they can embed their genome in an arbitrary place in the genome of an infected cell, causing mutations that lead to malignant cell degeneration. About 20 years ago, clinical trials of gene therapy for severe combined immunodeficiency associated with the X chromosome were conducted in France using a modified virus that causes leukemia in mice. In nine out of ten patients, the immunodeficiency disappeared, but three of them also developed leukemia during the three years of testing. One of the patients died. This case slowed down the development of gene therapy for a long time, but in the last few years, when more reliable viruses for gene transfer appeared, it seemed that such an obstacle was overcome.
Lentiviruses were considered more reliable in this respect compared to retroviruses used twenty years ago. But in 2019, it was reported that a monkey receiving lentiviral gene therapy developed a condition similar to leukemia. So it can be assumed that the risk of cancer has not been eliminated completely.
According to Bluebird bio, its specialists have not yet established where in the genome of a patient with AML the virus has embedded its genetic material. If the viral DNA got close to one of the genes that affect the likelihood of leukemia, it may have changed the activity of this gene and provoked the disease. It will take several weeks to verify this. At the same time Bluebird bio suspended sales of Zynteglo in Europe. Although this therapy is not aimed at sickle cell anemia, but at beta-thalassemia, it uses the same type of viral vector. The value of the company's shares fell by 38% during the day.
A similar disturbing news was announced in December last year. Then a patient with hemophilia, who was injected with a viral vector carrying a therapeutic gene during clinical trials, developed a liver tumor (hepatocellular carcinoma) a little over a year later. The Dutch company UniQure then also stopped testing to find out the causes of the disease.
Experts believe that the fault of the viral vector in this case is unlikely. The patient had liver diseases predisposing to the occurrence of carcinoma. In addition, the adenoassociated viruses, to which the therapeutic one belonged, are considered the safest in this regard. They are not embedded in the patient's genome, and the DNA they deliver floats freely in the cytoplasm of the cell. However, in rare cases, as animal studies have shown, such viruses are still able to introduce their genetic material into the genome of a cell. In particular, the adenoassociated virus caused hepatocarcinoma in newborn mice. There is also a possibility that the patient already had a slow-growing liver tumor provoked by hepatitis he had previously suffered, and the adenoassociated virus could have embedded itself in the DNA of his liver cells in such a way as to stimulate faster tumor growth. UniQure has promised to conduct the necessary research to test these hypotheses in a few months.
The news of gene therapy in the last few years resembled a summary from the battlefields of a victorious army. It was reported about successful experiments on animals for the treatment of various kinds of genetic and oncological diseases, about the encouraging results of clinical trials, about the official approval of genetic therapy methods. The current news reminds us that the successes of science are never easy. It is worth mentioning that now in the arsenal of gene therapy there are methods where viral vectors are not used, for example, CRISPR genome editing. Last year, this method showed promising results in the treatment of sickle cell anemia. But CRISPR itself is theoretically capable of causing non-targeted effects, and it will take at least several more years to understand how safe it is for patients.
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