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Q: I read your article on gene therapy a few weeks ago and recently, I read an article that said it is currently used to treat sickle cell disease. Does this mean that sickle cell disease is cured?
A: We both have copies of each gene, inherited from our mother and one from our father. Each gene is a strand of DNA divided into three nucleotides forming a codon. The codons specify the specific amino acids used to build the proteins that make up our cells, hormones, enzymes, and so on. Some people have an incorrect nucleotide in a codon of their hemoglobin gene (hemoglobin is the protein in red blood cells, red blood cells). , which carries oxygen). For example, HbS (sickle hemoglobin) has a codon that specifies valine instead of glutamine in sixth position on the beta-globin chain of hemoglobin.
In sickle cell disease, the two genes for hemoglobin are HbS (one of each parent). People with HbS gene and normal gene have a sickle cell trait; Although it usually acts of a benign condition, it means that there is a fifty percent chance of pbading the HbS gene to their child.
HbS is very common among African Americans. one in twelve is carrying the gene and one in 400 has SCD. In total, about 100,000 Americans have CPD and two million sickle traits.
When a fetus is in the uterus, it produces in its red blood cells a fetal hemoglobin that binds very strongly to oxygen (more strongly than the adult hemoglobin of its mother), which which allows the growing fetus to "pull" oxygen from its mother's blood (if it was not the case, the fetus would do it). not being able to charge your own red blood cells with mom's oxygen). About 6 months after birth, fetal hemoglobin is completely replaced by the baby's adult hemoglobin. It is for people with MS that the symptoms and complications of their disease can begin to manifest.
SCD can cause the stiffness of the patient's red blood cells and give them a sickle-shaped (hence the name of the disease) after administering the oxygen that they carry. This can destroy some of the red blood cells, so anemia and problems badociated with high turnover of red blood cells (such as gallbladder disease) are common.
In addition, a rigid sickle-shaped RBC can block small blood vessels and block blood flow. This causes a lack of oxygen in the tissues or organs that these vessels feed (ischemia), which can lead to temporary or even permanent lesions. The symptoms and complications of MSC depend on where the vessel blockage occurs. Ischemia to muscles or bones can cause pain, the most common symptom in patients with MCS. A stroke, kidney failure, infections (because the spleen becomes non-functional), and complications to the lungs, eyes, heart, and bones can also occur. Many other conditions and complications are also possible.
Given the high prevalence of MSC and its many possible complications, it is not surprising that it makes more than 200,000 emergency room visits each year. Two-thirds involve painful attacks, about 10% of chest pain, 5% of cases of fever or infections and 5% of respiratory problems. Between one-quarter and one-third of these patients require hospitalization for additional care.
Newborns in the fifty states are now screened for MCA, which is therefore most often diagnosed at birth. SCD patients should be followed by a health care provider with monitoring and treatment expertise, as early intervention can minimize (or at least delay) some of the complications.
The current treatment for patients with MCS includes regular examinations (including close monitoring of blood pressure and eye exams), periodic tests to help identify developing problems (such as blood tests for check the functioning of organs, cardiac echocardiograms and other tests), immunizations against certain infections (such as pneumococci), in addition to routine vaccinations, certain vitamins (such as folate) and other treatments (eg , chronic antibiotic therapy is recommended for all SCD children for at least five years and for some patients even longer to minimize infections and for some patients). hydroxyurea or other drugs to reduce painful crises). By receiving periodic blood transfusions, the risk of subsequent stroke can be reduced in 10% of MCA patients with stroke at the age of 20 and the 25% of patients with stroke. 39, a stroke at the age of 40, and renal failure may require dialysis. Acute flares require treatment on a case by case basis.
Despite proper care, the life expectancy of patients with MCS is reduced, but new treatment strategies offer hope.
An aggressive therapeutic option is to destroy the patient's stem cells (using chemotherapy and whole body radiation) and replace them with the donor stem cells so that the patient produces normal red blood cells from the donor's hemoglobin.
New approaches to gene therapy have already been tested in clinical trials, including:
genetically modify the patient's cells to "reactivate" the production of fetal hemoglobin red blood cells (by blocking the gene responsible for stopping the production of fetal hemoglobin).
– Take stem cells from the patient and genetically modify them using a viral vector to insert the correct gene into the nucleus of the stem cell. This would allow the cell to start producing normal hemoglobin, even if it remains the wrong codon (and thus some sickle cell production).
– Take the patient's stem cells and modify them genetically (using CRISPR as I described in a recent column) by cutting the incorrect codon and inserting the correct one.
Although it is too early to say that there is a cure for MSC, the hope that it will soon become a reality has never been so strong.
Jeff Hersh, Ph.D., M.D., can be reached at [email protected]
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