New Genetic Target for Sickle Cell Disease Therapy

Sickled and other red blood cells. Image by EM Unit, Royal Free Hospital School of Medicine. Wellcome Images.

Researchers have identified a gene involved in the inherited blood disorders sickle cell disease and thalassemia. The discovery identifies a potential new target for therapies that could dramatically alter the course of the disorders.

Sickle cell disease is the most common inherited blood disorder. It affects approximately 70,000 people in the United States, primarily African Americans. Worldwide, it affects millions of people.

The protein hemoglobin is involved in both sickle cell anemia and thalassemia. Found in red blood cells, this protein carries oxygen to the body's tissues. In sickle cell disease, hemoglobin is abnormal and sticks together, causing red blood cells to become stiff and sickle-shaped. The deformed cells block blood vessels and rob tissues of necessary blood and oxygen. In thalassemia, the body has trouble producing adult forms of hemoglobin.

Treatments developed over the past 3 decades have helped to double the life expectancy of sickle cell disease patients between 1972 and 2002. These treatments include medications, blood and bone marrow transfusions and other procedures to relieve symptoms and prevent complications. However, they do not cure the disorder.

Previous studies have shown that patients with sickle cell disease who continue to produce higher levels of fetal hemoglobin (HbF) have milder forms of sickle cell anemia. Likewise, higher levels of HbF reduce the severity of thalassemia. Scientists have thus been seeking ways to increase HbF production in patients with both disorders.

Earlier this year, researchers at Children's Hospital Boston and Dana-Farber Cancer Institute reported that several gene variants were associated with HbF levels in genome-wide association studies. Variations in a gene called BCL11A were found to have the greatest effect. Their further investigations of BCL11A were supported by NIH's National Heart, Lung and Blood Institute (NHLBI) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), along with the Howard Hughes Medical Institute.

In the online edition of Science on December 4, 2008, the researchers confirmed the significance of BCL11A. They reported that suppressing BCL11A in cultured human red blood cells causes HbF production to improve dramatically. This new finding provides important insight into the body's switch from producing fetal hemoglobin to adult hemoglobin.

One available drug, hydroxyurea, is already known to boost HbF levels and reduce the damaging effects of sickle cell disease. Its use is limited, however, because not all patients respond to the drug, and there are short- and long-term adverse effects. The new findings identify a highly specific target for potential therapies that directly affect the natural processes that help to raise HbF levels. Targeted therapies could offer greater benefits and fewer side effects than currently available therapies.