A Potential New Therapy for Sickle Cell Disease

Dana-Farber exterior. Image provided.

Sickle cell disease affects approximately 90,000 to 100,000 people in the United States and millions more worldwide. According to the National Institutes of Health, sickle cell anemia is the most common form of sickle cell disease, a serious disorder in which the body makes sickle-shaped red blood cells. “Sickle-shaped” means that the red blood cells are shaped like a crescent. Normal red blood cells are disc-shaped, and look sort of like a doughnut but without holes in the center.

Normal red blood cells contain an iron-rich protein called hemoglobin which carries oxygen from the lungs to the rest of the body. Sickle cells contain abnormal hemoglobin called sickle hemoglobin. Sickle hemoglobin is what causes the cells to develop a sickle, or crescent, shape. While normal red blood cells flow freely through the blood vessels, sickle cells are stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and organs and blocked blood flow can cause pain and organ damage. This can also raise the risk for infection.

A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates hemoglobin production. The discovery was published last week the journal, Science.

According to the press release:

Prior work by Dr. Stuart Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce fetal hemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle hemoglobin. BCL11A is thus an attractive target for treating SCD.

“This finding gives us a very specific target for sickle cell disease therapies,” said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. “Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.”

“This is a very exciting study,” said Feng Zhang, PhD, a molecular biologist and specialist in genome engineering at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, who was not involved in the study. “The findings suggest a potential new approach to treating sickle cell disease and related diseases, one that relies on nucleases to remove this regulatory region, rather than adding an exogenous gene as in classic gene therapy.”