Scientists have taken a potentially important step toward a therapy for sickle cell disease, a common genetic disorder characterized by malformed red blood cells. By forcing adult mice with sickle cell disease to produce a fetal version of the hemoglobin molecule that carries oxygen in blood, a research team has eliminated symptoms of disorder in the animals.
Millions of people around the world, most of them of African origin, suffer from sickle cell disease. They have a disruptive mutation in the gene for the blood cell molecule hemoglobin; as a result, their red blood cells typically take on a sickle shape, which causes them to clog up blood vessels, leading to intense pain, especially in the long limb bones. The average life span of a person with sickle cell disease is just 42 years for men and 48 years for women.
The potential new therapy is based on a well-known facet of the disease; its symptoms become apparent when babies are around 6 months old. Over half a century ago, scientists realized that's because the sickle cell mutation affects only the "adult" version of hemoglobin. This version is produced by two genes encoding hemoglobin subunits, but a newborn baby still uses fetal hemoglobin, a different version of the molecule in which the genes for the hemoglobin subunits are typically free from mutations. Researchers also discovered that a little bit of fetal hemoglobin, just over 1% of a person's total hemoglobin, generally courses through human veins our entire lives and that sickle cell patients who have more than usual, over 15%, have milder symptoms.
Recently, scientists have uncovered many of the molecules in the pathway that control the switch from fetal to adult hemoglobin, opening the door to new therapies; if you could prevent the switch from happening, or reverse it, and let people with sickle cell disease use fetal hemoglobin for life, that should reduce symptoms. The problem is that many of the factors driving the hemoglobin switch also have other crucial roles in red blood cells and in other parts of the body; knocking them out creates severe new problems.
But now, a team led by hematologist Stuart Orkin of the Howard Hughes Medical Institute and Harvard Medical School in Boston may have found the perfect target: a gene called BCL11A that produces a so-called transcription factor that helps shut down fetal hemoglobin production. Mice that completely lack BCL11A die soon after they are born, but when the team disabled BCL11A only in the red blood cells, the animals developed normally and produced blood with fetal hemoglobin levels at nearly 30%.
To investigate BCL11A's therapeutic value, Orkin's team turned to a mouse model for sickle cell disease. These mice have their hemoglobin genes removed and replaced with the mutated human version, saddling them with many of the same problems as human sufferers, including immature, short-lived, and sickle-shaped red blood cells; anemia; reduced blood flow; and an enlarged spleen. Silencing the BCL11A gene largely reversed those symptoms, with no apparent side effects, the group reports today online in Science.
This rodent proof of principle suggests that turning off BCL11A in people with sickle cell disease should allow them to produce enough fetal hemoglobin to reduce or eliminate their symptoms. "Now we've identified the target and the focus should be on hitting it," Orkin says. One option would be to shut down the expression of BCL11A, using small pieces of RNA, in blood-forming stem cells that would then be given to a person with the disease; another would be to inhibit the action of BCL11A directly using a more traditional, and possibly more practical, small-molecule drug.
"This [study] is extremely important," says hematologist Alex Felice of the University of Malta and Mater Dei Hospital, who has studied the genetics of a related blood disorder. "It replicates in a living organism data that might be useful to deliver new drugs for the treatment of sickle cell disease and other blood disorders." Felice notes, however, that in humans "BCL11A is expressed in other blood cell types," which means that silencing it with treatments could lead to complications not seen in the current mouse study. "Mice are mice and man is man," he cautions.