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We all rely on hemoglobin in our red blood cells to carry oxygen to the body's tissues. In children with sickle-cell disease, hemoglobin is abnormal, forming long chains that make red blood cells stiff and sickle-shaped. In thalassemia, the body's ability to produce hemoglobin at all is severely compromised. Both disorders cause anemia that can range from mild to life-threatening.
Now, Stuart Orkin, MD, a Howard Hughes Medical Institute investigator in Children's Hospital Boston's Division of Hematology/Oncology, and Vijay Sankaran, an MD-PhD student in Orkin's lab, have identified a way to compensate for this problem: getting red blood cells to make another type of hemoglobin that normally stops being made after birth.
At birth, the fetal form of hemoglobin, known as HbF, comprises 50 to 95 percent of a child's hemoglobin. Then there's a gradual switch to adult hemoglobin production. But some people retain the ability to produce HbF, and it's known that they have much milder forms of sickle-cell disease and thalassemia. But until now, there's been no good direct therapy to reactivate HbF production.
Last July, Orkin, Sankaran and collaborators reported five DNA sequence variants (altered strings of genetic code) that correlated with HbF levels and disease severity in a group of 1,600 patients with sickle-cell disease. And on Dec. 4, in the online Science Express, Orkin and Sankaran reported that a gene within one of these variants, called BCL11A, directly suppresses HbF production. When they suppressed BCL11A itself in red-blood-cell precursors, the cells began making HbF in large amounts.
"It's pretty clear that this gene is a silencer of fetal hemoglobin," says Orkin. "If you could knock it down to a low level, you could turn on fetal hemoglobin."
Orkin and Sankaran are conducting further studies to figure out how to target BCL11A therapeutically. If a strategy is found, it could potentially transform sickle-cell disease and beta-thalassemia into benign or nearly benign conditions. Even a modest increase in circulating HbF could ease symptoms substantially, they say.
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