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.