Do you know anybody with sickle cell disease? Sickle cell disease is the most common genetic blood disorder in the world. 70,000 to 100,000 Americans have it. It’s very likely that you know of someone who suffers from the disease or carries the gene.
Sickle cell anemia, a form of sickle cell disease, is caused by a gene mutation that changes the shape of the hemoglobin protein. The shape change causes blood cells which should be round, to be a sickle, curved shape. The deformed cells can clog blood vessels, causing severe pain and other dangerous symptoms. Another form of sickle cell disease is called beta-thalassemia which occurs when the body doesn’t produce enough hemoglobin and red blood cells, leading to low oxygen levels. As a result, children experience growth issues and fatigue.
CRISPR Therapeutics and Vertex have created a treatment called exa-cel, which uses gene editing to cure the disease for at least a year. In December of 2023, the FDA approved this treatment, making the U.S. the second country to approve a CRISPR therapy, following the U.K in November. A company called bluebird bio created another type of gene therapy called lovo-cel, which was approved by the FDA as well.
In exa-cel, the CRISPR system targets the genes that produce hemoglobin. Sickle celled anemia is caused by mutations in the gene HBB. The mutation distorts the structure of hemoglobin, which is what causes the blood cells to to have a curved shape instead of round. Exa-cel helps Cas9, an enzyme, target a gene called BCL11A. This gene stops the body from making a type of hemoglobin only found in fetuses. With Cas9, exa-cel cuts its DNA, which switches off BCL11A in bone marrow stem cells, where red blood cells are produced. As a result, the cells start making the fetal hemoglobin they were originally unable to produce, leading to the creation of healthy-shaped red blood cells. In this new treatment, doctors take out a person’s bone marrow stem cells, edit them with exa-cel, dispose of the rest of their untreated bone marrow, and then put the edited cells back in.
As learned in AP Biology, deletions in DNA can change the process of gene expression. The first part of gene expression is transcription, which happens in three steps: initiation, elongation, and termination. In initiation, the enzyme RNA polymerase binds to a region on a gene called the promoter. This then signals the DNA strand to unwind which allows the RNA polymerase to read the bases. Then in elongation, the RNA polymerase reads the DNA and makes an mRNA strand with complimentary base pairs. During termination, the RNA polymerase crosses a stop sequence, the mRNA strand is complete, and it detaches from the DNA strand. The mRNA then goes on to translation, which is when it is read to make proteins. When exa-cel deletes the DNA that codes for the BCL11A gene, it is never transcribed or translated, it is never expressed, and therefore the body can produce hemoglobin.
Since these modified cells replenish the body over time, exa-cel is seen as a “curative” treatment that is expected to last for the recipient’s lifetime. However, Vertex and CRISPR Therapeutics have only monitored most of their trial participants for less than two years. While nobody is certain that the treatment is permanent and without side effects, this type of gene editing is very significant to the scientific world, and could help thousands of people!
Exa-cel has be tested in about 100 individuals diagnosed with either sickle cell anemia or beta-thalassemia. However, in 2019, the FDA granted the companies a “fast-track” approval, enabling them to test the therapy in smaller groups than what is typically required.
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