Reawakening a dormant gene could ease sickle-cell disease and thalassemia

Researchers at Children's Hospital Boston and Dana-Farber Cancer Institute have identified a way to get red blood cells to produce a form of hemoglobin normally made only before birth or by young infants. This could potentially transform sickle-cell disease and beta-thalassemia -- life-threatening inherited anemias -- into benign or nearly benign conditions.

After birth, babies gradually switch from producing fetal hemoglobin (HbF) to an adult form. From population studies, it?s been known for many years that people who retain the ability to produce HbF have much milder forms of anemia. Attempts to develop therapies to reactivate HbF directly have been hampered by a lack of understanding of how HbF production is switched off. The drug hydroxyurea often raises HbF in patients, but responses are not uniform and there are potential side effects.

Seeking a better approach, researchers Stuart Orkin, MD, a Howard Hughes Medical Institute investigator at Children's Hospital Boston, and Vijay Sankaran, an MD-PhD student in Orkin's lab, in collaboration with researchers at the Broad Institute of Harvard and MIT, capitalized on comprehensive gene association studies that identified DNA sequence variants (altered strings of genetic code) that correlate with HbF levels. In a study published last July, they identified five variants that influence HbF levels and disease severity in a group of 1600 patients with sickle-cell disease, the most common inherited blood disorder in the United States.

The variant with the largest effect on HbF levels contains a gene called BCL11A. Located on chromosome 2, it encodes a transcription factor, a protein that regulates activity of other genes. This turned out to be a valuable lead.

In the new study, led by Orkin and Sankaran, the team showed that BCL11A directly suppresses HbF production. When the researchers suppressed BCL11A itself in human red-blood-cell precursors, the cells began making HbF in large amounts.

"This is one of very few instances in the gene association field where one has been able to take a candidate gene and figure out what it's doing," says Orkin, the study's senior investigator who is also a professor of pediatrics at Harvard Medical School and chair of pediatric oncology at Dana-Farber. "It's pretty clear that this gene is a silencer of fetal hemoglobin. If you could knock it down to a low level, you could turn on fetal hemoglobin."

"The discovery of a single gene that profoundly affects fetal hemoglobin levels represents a major breakthrough in the quest for effective therapies for sickle cell disease and thalassemia," notes Elizabeth G. Nabel, MD, director of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, which helped support the study. "Researchers can now direct their efforts at developing novel therapies aimed at a specific target that could dramatically alter the course of these often devastating blood disorders. This news should bring great hope to the millions of people worldwide affected by sickle cell disease and thalassemia."

Increasing levels of HbF would compensate for abnormal or insufficient adult hemoglobin in sickle-cell anemia or thalassemia, easing symptoms and in some cases achieving a virtual cure, the researchers say. The drug hydroxyurea, used in some patients with hemoglobin disorders, often raises HbF levels, but the increases are modest, it doesn?t work in all patients, it can cause toxicity, and no one knows how it works.

"While it's been demonstrated that increased levels of HbF ameliorate the severity of sickle cell disease and beta-thalassemia, no direct strategies have yet been developed to increase HbF in these diseases," says Sankaran. "By reducing BCL11A expression or activity, we may be able to develop targeted therapies."

Hemoglobin is the protein in red blood cells that carries oxygen to the body's tissues. In 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 is severely compromised. The hallmark of both disorders is anemia that can range from mild to life-threatening. Sickle-cell disease can cause severe pain and eventual organ damage as the abnormal, sickle-shaped cells block blood vessels, robbing tissues of their blood supply; beta-thalassemia requires frequent blood transfusions and then chelation therapy to rid the blood of excess iron that also leads to organ failure.

At birth, HbF comprises between 50 to 95 percent of a child's hemoglobin before the switch to adult hemoglobin production. The fetal form is thought to be an adaptation to the low oxygen in the fetal environment. Fetal hemoglobin has a higher affinity for oxygen, enabling it to pull oxygen more easily from the mother?s circulation.

Are there potential side effects from boosting fetal hemoglobin levels? No, the researchers say. "Some people with rare genetic deletions have 100 percent fetal hemoglobin, and they're perfectly normal," says Orkin.

Orkin and Sankaran are conducting further studies to figure out how the switch from fetal to adult hemoglobin production occurs and how to target BCL11A therapeutically. "Improved understanding will permit the design of therapies for reactivation of HbF in patients with sickle-cell disease or thalassemia," says Orkin.

This study was supported by grants from the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Howard Hughes Medical Institute.

 

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