Will gene therapy help sickle cell anemia patients?
In the progenitor cells of erythrocytes of people with sickle cell anemia
you can start the formation of fetal hemoglobin
ABC Magazine based on the materials of Dana-Farber Cancer Institute:
Discovery of new gene regulator could precisely target sickle cell diseaseA group of researchers from the Department of Pediatric Oncology at the Dana-Farber Institute in Boston, USA (Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston) has discovered a new potential genetic target for the treatment of sickle cell anemia.
This target is an enhancer, a DNA element that regulates the activity of the BCL11A switch protein synthesis, which, in turn, regulates the production of hemoglobin. When the enhancer is suppressed, the synthesis of fetal hemoglobin sharply increases.
Sickle cell anemia is a hereditary disease in which hemoglobin molecules acquire a special crystalline structure – the so–called hemoglobin S. Erythrocytes carrying hemoglobin S instead of normal hemoglobin A have a characteristic sickle shape under the microscope, for which this disease got its name.
Erythrocytes carrying hemoglobin S have reduced resistance and reduced ability to transport oxygen, therefore, the destruction of erythrocytes in the spleen is increased in patients, their life span is shortened, hemolysis is increased and there are often signs of chronic oxygen deficiency.
Dr. Stuart Orkin (MD) and his colleagues have previously reported that BCL11A can trigger the formation of fetal hemoglobin in erythroids (progenitor cells of erythrocytes that have not yet lost the nucleus and, accordingly, the ability to synthesize protein). In patients with sickle cell anemia, fetal hemoglobin is not affected by the mutation, and its production can reduce the manifestations of the disease.
The BCL11A protein has come to be seen as a promising target for drug development. This protein plays an important role in many other processes, for example, in the production of B-lymphocytes, therefore it is quite risky to directly influence its production or activity. The enhancer discovered by Orkin and colleagues regulates BCL11A exclusively in erythroids. Turning off the enhancer in them will lead to a decrease in the function of BCL11A and the beginning of fetal hemoglobin production without consequences for other hematopoietic cells.
There is clinical data on the role of the enhancer: in some patients with sickle cell anemia, there is an increased content of fetal hemoglobin and this corresponds to a better prognosis of the course of the disease. The researchers confirmed that such patients have natural mutations that reduce the function of the enhancer. Accordingly, their BCL11A activity decreases and fetal hemoglobin production increases.
According to the authors of the work, modern methods of influencing genetic elements in intact cells open the door to the treatment of many diseases associated with hemoglobin. Moreover, unlike traditional approaches to gene therapy, in this particular case it is not necessary to introduce new genes into the cells of the body and regulate their work – it is enough only to cut out the regulatory DNA site with nucleases.
Article by Bauer et al. An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level is published in the journal Science.
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