MOSCOW, November 10, Tatyana Pichugina.Dozens of patients with sickle cell anemia and beta thalassemia have received gene therapy developed by Swiss scientists. If the trial results are approved in the United States, a drug based on the CRISPR-Cas9 DNA editor will hit the market for the first time in the world. What are its advantages and what are the concerns?
From the laboratory to practice
At the beginning of this century, geneticists discovered a powerful genome editing system using Cas9 protein enzymes, found in bacteria . These molecules cut a section of DNA and insert a viral sequence called CRISPR (Clustered Regularly Short Palindromic Repeats). It turned out that these enzymes also act in multicellular organisms, including mammals.
The origins of the method were the French geneticist Emmanuelle Charpentier, who founded the company CRISPR Therapeutics in 2013.
“I hope that a technology will appear that can deliver the CRISPR-Cas9 system into cells and tissues to treat severe hereditary diseases,” Charpentier said two years later in an interview with New Scientist magazine.
The first phase of clinical trials of the drug CTX001 (now exa-cel) based on CRISPR-Cas9, developed by Charpentier, began in 2018. Two patients with beta thalassemia and sickle cell anemia, rare hereditary blood diseases caused by hemoglobin abnormalities, received treatment.
Testing a gene editor on patients
Diseases that can be cured by correcting just one gene are most suitable for developing gene therapy. In practice, drugs are already used to treat spinal muscular atrophy, severe combined immunodeficiency, and hereditary retinal dystrophy. Last year, two treatment regimens for blood diseases, hemophilia A and B, were approved for use in the United States.
All of these methods use the same approach—the virus delivers a healthy copy of the gene into the cell. The synthesis of healthy protein starts, and the disease recedes.
Exa-cel therapy works differently. Hematopoietic stem cells are selected from the patient and the BCL11A gene is edited ex vivo (outside the body) using CRISPR-Cas9. This section of DNA suppresses the synthesis of intrauterine hemoglobin (fetal), which delivers oxygen to the blood in the first years of life. If you “turn off” BCL11A using “gene scissors,” then fetal hemoglobin will begin to be produced again and gradually displace the pathogenic variant. The edited cells are transfused back into the body.
The first patient was a 19-year-old girl with beta thalassemia who required annual blood transfusions. After gene therapy for almost 22 months, she developed 32 complications, two of them severe.
The second drug was received by a 33-year-old woman with sickle cell anemia (hereinafter referred to as SCA), who was also treated with blood transfusions. Over almost 17 months of observation, she suffered more than a hundred different complications, including three severe ones. However, the hemoglobin level and other blood parameters returned to normal, and painful attacks (vaso-occlusive crises) disappeared. The trial report was published in the oldest medical journal, The New England Journal of Medicine.
The results of the second phase of clinical trials were presented last June at the Congress of European Hematologists. They included 44 patients with beta thalassemia and 31 people with SCD. All received a single blood transfusion edited with exa-cel.
In the first group, 95 percent of participants no longer required traditional treatment, while the rest sharply reduced its volume. Two suffered serious complications that were treated. Patients of the second group completely got rid of vaso-occlusive crises. At the same time, the level of fetal hemoglobin in all of them increased by 40 percent.
Who is the new medicine intended for
At the end of October, experts from the US Food and Drug Administration began examining the results of trials of the drug exa-cel for the treatment of sickle cell anemia. Manufacturers of the drug are CRISPR Therapeutics and Vertex Pharmaceuticals (Boston, USA).
This pathology manifests itself from an early age, its cause is a violation of hemoglobin synthesis.
“The disease is caused by a point mutation in the beta-globin gene, which leads to a change in the properties of hemoglobin. It becomes gel-like, which is why the shape of the red blood cell changes to sickle-shaped. This leads to disruption of blood microcirculation, a decrease in the binding capacity of hemoglobin in relation to oxygen,” — explains hematologist, researcher at the Department of Orphan Diseases of the National Medical Research Center for Hematology of the Russian Ministry of Health Nina Tsvetaeva.
Patients suffer from repeated pain crises — pulmonary, bone, liver, vascular, infectious. In their absence, people generally do not need therapy, the specialist adds.
“Prevention of crises is very important. It is necessary to avoid excessive physical activity, dehydration, climbing to an altitude of more than 1500 meters, bad habits, as well as consanguineous marriages. A radical method of treatment is hematopoietic stem cell transplantation, which is advisable to carry out at a young age before serious complications arise,” — says Tsvetaeva.
According to her, the disease is common in regions prone to malaria. In Russia it is extremely rare. Over the past 20 years, the National Medical Research Center for Hematology has identified only 17 cases based on the results of molecular genetic diagnostics.
“Nine people were treated for crises, among them only one Russian,” the hematologist cites statistics.
In the United States, approximately 100 thousand people suffer from sickle cell anemia. The overwhelming majority are people whose ancestors came from Equatorial Africa. The pathology is also common among residents of Spanish-speaking regions of South and Central America, the Caribbean, Saudi Arabia, India, Turkey, Greece and Italy. There are four to five million carriers of the abnormal hemoglobin gene in the world.
Long-term consequences
Whether the new gene therapy will be approved will become clear in early December.
“The key condition for making a decision is the safety of the drug. But there is not enough information on this,” Nature quotes expert Mark Walters, a pediatrician at the University of California, San Francisco.
One of the concerns is errors when stitching together DNA strands cut by the CRISPR-Cas9 editor. The genome has a built-in repair mechanism, but sometimes it fails. In addition, the editor can accidentally cut a similar section of DNA, which, in turn, can lead to oncology or other serious diseases. Manufacturers of the drug claim that the risk of such an error is zero, but this requires proof.
The fact is that the genomes of African Americans are not fully represented in the databases that were searched to identify potentially similar sections of DNA. In addition, experts are concerned about the small number of patients who participated in clinical trials, as well as the insufficient diversity of cell lines subjected to the experiment.
There are grounds for doubt. Two patients with sickle cell disease who received viral vector-based gene therapy developed blood cancer. The study showed that the cause is not a virus, but edited blood stem cells.
Scientists plan to follow people who received the CRISPR-Cas9 drug for another 15 years to track long-term effects. In the meantime, if the drug is approved, patients will be informed about the possible risks.