December 04, 2008
A New Genetic Switch May Boost Treatment Options for Sickle Cell Disease
Howard Hughes Medical Institute (HHMI) researchers have discovered a genetic switch that shuts off production of a fetal form of hemoglobin shortly after birth. By reducing or turning off the regulatory protein responsible for flipping that switch, the researchers can reactivate the dormant fetal hemoglobin gene--possibly with therapeutic benefits for patients with the life-threatening anemias sickle cell disease and beta-thalassemia.
Normally, hemoglobin production shifts from a fetal form to an adult form shortly after birth. But some individuals naturally continue to produce fetal hemoglobin as adults, and in patients with sickle cell disease and beta-thalessemia, the presence of fetal hemoglobin is associated with milder forms of the disease. But until now, researchers have not known how to manipulate the expression of human globin genes.
“When we silenced BCL11A in these cells, we observed that fetal hemoglobin increased dramatically, up to 40 percent. This is considerably higher than is needed to ameliorate sickle cell disease or beta-thalassemia.”
The new work, carried out by HHMI investigator Stuart Orkin and his colleagues at Children's Hospital, Boston and Dana-Farber Cancer Institute identifies a gene called BCL11A as the first regulator of the human hemoglobin switch. As such, Orkin says, BCL11A is a logical target for potential drugs that manipulate that switch. He cautions, however, that developing these drugs will be challenging and take at least several years.
Orkin's group collaborated on the research with scientists at Harvard Medical School, the Broad Institute, and UCLA. The team reported its findings on December 4, 2008, in Science Express, which provides rapid electronic publication of select articles from the journal Science.
Both sickle cell disease and beta-thalassemia arise from abnormalities in beta-globin--a component of the form of hemoglobin that carries oxygen in adult blood. Sickle cell disease arises from a single letter change in the DNA sequence that encodes the beta-globin protein. This causes production of a form of hemoglobin that tends to aggregate and cause red blood cells to become deformed. The misshapen red blood cells clump together and further deteriorate, leading to clogged blood vessels that can cause strokes and organ damage. The only permanent cure for sickle cell disease is a bone marrow transplant to provide new cells capable of producing normal beta-globin. However, due to the lack of compatible bone marrow donors and potential complications of the procedure, transplants are not widely used.
In contrast, beta-thalassemia is caused by inadequate production of adult beta-globin. This can be caused by many different mutations in the gene, and reduces the blood cells' ability to carry oxygen.
Researchers have long known that symptoms of both diseases are alleviated in patients when the type of hemoglobin present in a developing fetus, called fetal hemoglobin (HbF), persists in red blood cells after birth. This fetal hemoglobin, which usually disappears after birth, contains a fetal globin protein called gamma-globin in place of adult beta-globin.
An FDA-approved therapy for sickle cell disease boosts HbF, which can compensate in part for the deficiency of normal adult hemoglobin. The therapy, is not effective in all patients, however, and is associated with significant side effects. Orkin and his colleagues hoped that a better understanding of how hemoglobin production is controlled might suggest new strategies for treatment.
Researchers first identified BCL11A as a potential regulator of fetal hemoglobin in genome-wide surveys of populations of normal individuals or those with sickle cell anemia or thalassemia, said Orkin. Those studies found that variations in the BCL11A gene correlate with different levels of residual HbF in adults. “Many gene-association studies have been reported, but it usually turns out that variants in the genes account for only a small percentage of variations in the disease,” he said. “But in this case, variations in BCL11A seemed to have a very strong effect on fetal hemoglobin levels. Also, this effect occurred across diverse human populations.”
Because Orkin's group knew that BCL11A repressed the activity of some genes in other cell types, it seemed reasonable that it might also be an important regulator of fetal hemoglobin production, he said. They found the full length BCL11A protein in red blood cells that produce adult hemoglobin, but cells that produce fetal hemoglobin made only a shorter form of BCL11A. Their experiments also revealed that the protein produced by BCL11A in adult red blood cells associated physically with other red cell regulatory proteins.
Their most significant discovery, Orkin said, was that shutting off BCL11A in human adult red blood cells reactivates the expression of fetal hemoglobin. “When we silenced BCL11A in these cells, we observed that fetal hemoglobin increased dramatically, up to 40 percent. This is considerably higher than is needed to ameliorate sickle cell disease or beta-thalassemia, since we know from clinical studies that an increase of only 10 to 20 percent is enough to have a beneficial effect.”
He noted that their research suggests that BCL11A is a “molecular rheostat” that controls the fetal globin gene. “This suggests that you could dial down BCL11A and get a concomitant rise in fetal hemoglobin,” said Orkin. “So, this is the first molecule that we can point to as a direct silencer of fetal hemoglobin.” Further, Orkin said his group's experiments showed that knocking down BCL11A did not impair the blood cells' development.
Drugs that interfere with the expression of the BCL11A gene or the activity of the BCL11A protein would offer a highly effective treatment for sickle cell disease and beta-thalassemia, he said. The finding could also lead to gene therapy to introduce a BCL11A-silencing RNA directly into bone marrow cells.
“Developing these treatments is going to be a long haul,” cautioned Orkin. “However, the fact that we have found this gene offers a highly promising start.”