Virtual Medical Centre

Turning back the clock in inherited anaemia

20 December 2008
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 haemoglobin normally made only before birth or by young infants. This could potentially transform sickle-cell disease and beta-thalassemia - life-threatening inherited anaemia - into benign or nearly benign conditions. The findings were published by the journal Science, in its online Science Express, on December 4.

After birth, babies gradually switch from producing foetal haemoglobin (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 anaemia. 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, capitalised 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 paediatrics at Harvard Medical School and chair of paediatric oncology at Dana-Farber. "It's pretty clear that this gene is a silencer of foetal haemoglobin. If you could knock it down to a low level, you could turn on foetal haemoglobin."

"The discovery of a single gene that profoundly affects foetal haemoglobin 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."