A recent study from the Boston Children’s Hospital reveals a new potential treatment option for patients suffering from a blood disorder called sickle cell disease (SCD)

SCD is a red blood cell disorder. Normally, red blood cells are round, which helps with their function as they move through small blood vessels to carry oxygen to all parts of the body. For patients with SCD, the red blood cells are deformed and have a resemblance to a C-shaped farm tool called a “sickle,” giving the disease its name. 

Normal red blood cells have a lifespan of about 120 days. However, with SCD, red blood cells only survive 10 to 20 days, due to the spleen. This organ is tasked with filtering the blood, specifically for infections, and cells affected by SCD become stuck in this filter and die. This can eventually lead to chronic anemia, as a result of decreased oxygen flow, as well as serious damage to the spleen, which can then result in an increased risk for infection.

The deformed shape of red blood cells can be traced to a mutation in the gene that directs the production of hemoglobin — an iron-rich compound that makes blood red and enables red blood cells to carry oxygen. A product of SCD, the abnormal hemoglobin causes red blood cells to become rigid, sticky and misshapen.

An additional problem with SCD is that when the malformed cells travel through small blood vessels, they can aggregate and cause blockages in the blood flow, eventually leading to clots. This results in pain and other serious problems such as infection, acute chest syndrome and stroke. 

SCD is passed on genetically and can be diagnosed either by a blood test at birth or through prenatal testing. SCD is often discovered during routine newborn screening tests and it is crucial to be diagnosed early as those with SCD are more prone to infection and other health problems that may require treatment. Signs of SCD generally appear around five months after birth, with symptoms and complications varying widely for each person. This results in the differences between treatment options as they depend largely on the individual’s symptoms. 

The majority of treatments are temporary, tailored towards the individual’s symptoms, pain and overall physical comfort. The main options available are blood transfusions and different medications, each treatment differing in their method of administration and range of side effects.

Previously, the only known cure for SCD was a bone marrow or stem cell transplant. Blood cells are made in the bone marrow, a soft, fatty tissue located inside the bone. A transplant involves removing healthy bone marrow cells from a donor and transplanting them into a patient. To avoid rejection of the donor cells, the bone marrow must be a close match — usually a family member. These transplants are risky, and thus only used when there is a severe case of SCD. 

The bone marrow transplant technique requires the patient to first undergo chemotherapy treatment to remove the patient’s own cells and prepare for the replacement with healthy cells. This can be extremely taxing on the body as the drugs used in chemotherapy can lead to tiredness and flu-like symptoms.

Now a possible alternative is being explored. A recent study was conducted by Dr. David A. Williams and his team at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. The trial showed promising results in its first patient, with Williams and his team using a new gene therapy approach. In this method, the production of fetal hemoglobin is initiated while preventing the production of the abnormal sickle form of adult hemoglobin. By increasing the amounts of fetal hemoglobin in the body, the level of blood cells affected by SCD decreases and the level of regularly shaped, healthy blood cells increases. Eventually, the body can make the transition to a healthier state with reduced signs of SCD.

Fetal hemoglobin (HbF) is the dominant form of hemoglobin present in the fetus during gestation. Fetal hemoglobin production decreases shortly after birth as it is blocked by BCL11A. Normally the body responds by increasing production of adult hemoglobin, but in people suffering from SCD, a mutated, sickled hemoglobin is produced. 

This trial focused on stopping the expression of the BCL11A gene, allowing the continued production of fetal hemoglobin. However, the researchers found that BCL11A plays an important role in blood stem cells. Once the BCL11A gene was silenced in mice with sickle cell disease, blood stem cells could not engraft to the bone marrow and eventually became depleted. Engraftment is when blood-forming cells start to grow and make healthy blood cells. If the blood stem cells fail to engraft, it could render gene therapy ineffective and also cause serious problems with blood development in general. To avoid this issue, the team of researchers engineered a version of the gene therapy that selectively targeted precursors to red blood cells.

With this solution, researchers found that the continued production of fetal hemoglobin after birth can reduce the severity of SCD. The Williams trial, however, marks the first time an approach targeting BCL11A has resulted in increased fetal hemoglobin production. 

This potential treatment would be a safer option with fewer severe side effects, providing hope for those with SCD.

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