Inherited forms of anemia may soon be treated by turning on a gene normally active only in the womb. Researchers report today in Science that they have discovered the molecular switch for activating the fetal form of hemoglobin—the iron-containing protein in red blood cells that transports oxygen—which could help alleviate the symptoms of genetic blood disorders, including sickle-cell anemia, which affects an estimated 70,000 people (mostly African-Americans) in the U.S.

This study "provides the first fairly targeted therapeutic opportunity for these patients," says Susan Shurin, a hematologist and acting director of the Division of Blood Diseases and Resources at the National Heart, Lung and Blood Institute (NHLBI) in Bethesda, Md., noting that it paves the way for new treatments.

Patients with sickle-cell disease generally only live into their 40s with few treatment options available beyond pain management and blood transfusions. Although the cancer drug hydroxyurea is prescribed to some sufferers, it is not always effective and increases the risk of infection. Over the years, a number of other drugs have been tested but turned out to be toxic or cause other damaging side effects.

Hemoglobin is a complex of four subunits; two of these subunits are produced from birth to death, whereas the other pair is first comprised of a fetal subunit type that switches after birth to an adult form. In vitro, the fetus produces hemoglobin from genes encoding gamma subunits. After birth, these genes are silenced and beta subunits replace them to form adult hemoglobin. Sickle-cell disease and β (beta) thalassemia—one of an inherited group of hemoglobin synthesis disorders—result from mutations in the adult beta subunits that diminish the capacity of red blood cells to carry oxygen.

In patients with sickle-cell disease, abnormal beta subunits cause red blood cells to stiffen and form clumps in blood vessels, leading to anemia, pain and organ damage from reduced blood flow.

Found in patients predominantly of Mediterranean, African, Middle Eastern and Asian descent, β thalassemia affects thousands of infants worldwide each year, according to the NHLBI. Mutations in the beta subunits of these patients result in lower levels of hemoglobin and fewer red blood cells, causing severe anemia, poor growth and bone abnormalities.

Because the mutations underlying these disorders are limited to the adult form of hemoglobin, reactivating fetal gamma hemoglobin could alleviate symptoms and restore oxygen transport in the body. In fact, rare individuals missing the beta subunit genes produce only fetal hemoglobin throughout their lives and are perfectly normal, says study leader Stuart Orkin, a hematologist at Children's Hospital Boston.

Using previous data, Orkin and his team identified the BCL11A gene as a candidate for controlling the molecular switch. "The effect of this gene on fetal hemoglobin levels was very strong," Orkin says, "cutting across populations of Europeans, Africans and Asians."

By examining adult blood cells in the laboratory, the investigators found that BCL11A actually silenced the fetal gamma gene. By eliminating the function of BCL11A, the researchers were able to reactivate fetal hemoglobin production by up to 40 percent in adult blood cells—more than necessary. "We don't need such a dramatic increase to help patients," Orkin notes, "even only 15 percent more fetal hemoglobin would benefit them."

The next step for the researchers is to design therapeutic strategies for enhancing fetal hemoglobin production. Although gene therapy could one day provide an avenue for blocking BCL11A in the bone marrow (where red blood cells are made), Orkin says, it is more likely that chemical screens will help identify drugs able to silence BCL11A in patients.

Shurin cautions that at least two years of development will be needed before the first human trials of any drug. One challenge facing researchers, she notes, is that BCL11A is also important for the development of some immune cells. Therefore, they must explore the effects of deactivating it on the body's ability to fight infections and other diseases—as hampering the gene's effects only in red blood cells would be difficult.

Orkin and Shurin agree that the importance of this study transcends its therapeutic potential. Not only does the work examine an important event in human development, but it is one of only a few studies that have successfully taken a candidate gene identified in genetic screens and determined its role in disease. As Orkin says, "it's a place to start."