Hope for Sickle Cell

Sept. 19, 2014

By Medical Discovery News

While sickle cell disease has long been studied, a recent discovery revealed that the disease significantly increases the levels of a molecule called sphingosine-1-phosphate (S1P), which is generated by an enzyme called sphingosine kinase 1 (SphK1). Inhibiting the enzyme SphK1 was found to reduce the severity of sickle cell disease in mice, which will hopefully lead to new drugs that target SphK1in order to treat sickle cell disease in humans.

Sickle cell disease is caused by a change in the gene that is responsible for a type of hemoglobin, the protein molecule in red blood cells that carries oxygen. This tiny change results in hemoglobin clumping together, changing the shape of red blood cells.

The name for sickle cell disease actually comes from misshapen red blood cells. Rather than being shaped like a disk, or a donut without a whole, sickle cells are shaped like a crescent, sort of bending over on themselves. The normal shape is critical to red blood cells’ ability to easily travel through blood vessels and deliver oxygen to cells and tissues. Sickle cells become inflexible and stick to each other, blocking the flow of blood through blood vessels.

Symptoms of the disease begin to appear at about four months of age. Normally, red blood cells live for about 120 days. Sickle cells only survive 10-20 days. Although the bone marrow tries to compensate for the rapid loss of red blood cells, it cannot keep up. The disease causes pain, anemia, organ damage, and possibly infections.

Although the symptoms and their severity vary, most people with sickle cell disease will have periodic crises lasting hours or days. Symptoms include fatigue, paleness, shortness of breath, increased heart rate, jaundice, and pain. Long-term damage can occur in the spleen, eyes, and other organs, and sickle cell disease increases the risk of stroke. People who only inherit one copy of the sickle cell hemoglobin gene have a milder case of the disease than those who inherit two copies, one from each parent.

Current treatments only reduce the number and the severity of crises using hydroxyrurea, blood transfusions, pain medications, and antibiotics. As the disease advances, dialysis, kidney transplants, eye surgeries, gall bladder removal, and other treatments may be necessary. The only cure for the disease is a bone marrow transplant, which is not an option for everyone.

So it’s pretty exciting that when scientists found that levels of S1P were elevated in mice with sickle cell disease, they inhibited the enzyme SphK1 to reduce the levels of S1P. As a result, red blood cells lived longer and had less sickling. The mice also had less inflammation and tissue damage, which would reduce damage to red blood cells and prevent symptoms of the disease. When they engineered sickle cell disease mice without the gene for the enzyme SphK1 that makes S1P, again the mice had less sickling and symptoms.

How does S1P influence sickling? Apparently, it binds directly to hemoglobin and reduces its ability to collect and carry oxygen, which causes the characteristic folding of cells. S1P has other roles in the body, so it is unknown whether inhibitors to SphK1 can safely and effectively be used in humans to treat sickle cell disease.

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Reducing Sickle Cell Disease

By Medical Discovery News

Feb. 25, 2012

Reversing Sickle Cell Disease

Human red blood cells do an amazing job – transporting needed oxygen to every part of the body. However, in some people, red blood cells are not smooth, round discs that move easily through the blood vessels. Instead, they are crescent or sickle-shaped, which not only block tiny blood vessels called capillaries, but break apart and die prematurely. For a person living with these deformed red blood cells, this results in pain, anemia, stroke, organ dysfunction and damage, and eventually death.

What’s interesting about this disease, called sickle cell, is it doesn’t afflict a developing fetus. The disease develops three to six months after delivery. Now researchers at Harvard Medical School in Boston and the University of Texas at Austin have found a way to get diseased adult mice to switch to their ability to make the healthy red blood cells they made as fetuses. This switch is a gene called BCL11A, and it affects the body’s production of fetal hemoglobin.

Healthy red blood cells are filled with hemoglobin, an iron-rich protein that carries oxygen from the lungs to the rest of the body. With sickle cell, an inherited disease, infants get two copies of a mutated gene that makes hemoglobin with a reduced ability to carry oxygen, and that form into long rods, stretching the cell into a crescent shape.

However, the cells don’t begin to sickle until an infant is a few months old. Researchers discovered that BCL11A switches the body from making fetal hemoglobin, which does not sickle, to adult hemoglobin, which does. Dr. Stuart Orkin, who led the team of researchers who identified BCL11A, found when they blocked the gene in diseased mice, the rodents’ bodies began producing fetal hemoglobin again. These cells did not sickle, and soon after, disease symptoms improved without compromising red blood cell production.

Remarkably, 85 percent of all the red blood cells had some fetal hemoglobin. Inside these cells, fetal hemoglobin represented 30 percent of the total hemoglobin. This is enough fetal hemoglobin to keep cells from sickling.

There is a drug called hydroxyurea, which helps the body produce fetal hemoglobin, but patients can suffer bad side effects. The only existing cure for sickle cell disease is a bone marrow transplant, but finding a match is challenging and the procedure is risky.

Considering the few treatments available to people with sickle cell, this latest discovery is significant. However, the method won’t be tried on humans for years because it’s unlikely the only function for BCL11A is as a switch for the production of fetal hemoglobin. Researchers must determine not only its other functions, but other consequences of turning it off. If this therapy works, it has the potential to make a significant impact since three to five million people worldwide suffer from sickle cell disease.

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