Steele Children's
Sickle Cell Anemia, other Blood Diseases, Suggesting New
Therapeutic Approaches
Feb. 22, 2006
From: Darci Slaten,
(520) 626-7217
Researchers at The University of Arizona Steele Children's Research
Center have discovered that the protein Sox6 is responsible for
silencing-or turning off-epsilon globin-the embryonic form of beta-globin in
hemoglobin. The researchers believe that if epsilon globin can be "re-expressed"
(turned back on), it can limit the harmful effects of sickle cell anemia and
beta-thalassemia, hereditary blood diseases that affect about 7 percent of the
population (primarily African Americans).
The
"Based on this discovery, we now have laid the
foundation to begin exploring ways to develop new therapies for sickle cell
anemia," Dr. Brilliant says.
Hemoglobin is the protein in red blood cells responsible
for transporting oxygen from the lungs to the rest of the body. Normal red blood
cells move easily through the blood vessels to deliver oxygen. In sickle cell
anemia, genetic mutations in adult beta globin cause the hemoglobin molecules to
stick together in long, rigid rods after they release oxygen. These rods cause
the red blood cells to become hard and sickle-shaped. When these sickle-shaped
red blood cells go through small blood vessels, they clog the flow, depriving
the body's cells of blood and oxygen. Side effects include anemia (low blood
count) pain episodes, strokes, eye and bone damage.
Hemoglobin consists of "alpha globins" and "beta
globins." During development from embryo to adult, beta-globins undergo
"beta-globin gene switching"- the transition from embryonic to fetal to adult
forms of beta-globin. This transition results in hemoglobins with a different
affinity for oxygen. Since sickle cell anemia and beta-thalassemia result from
mutations in the adult beta-globin, providing small amounts of normal embryonic
or fetal beta-globins can alleviate some of the detrimental effects of the
abnormal adult globins, as is found in sickle cell anemia.
This currently is accomplished through a
chemotherapeutic approach that uses the drug hydroxyurea. "This chemical causes
re-expression of earlier forms of globin that have been turned off in the adult,
providing needed relief," says Dr. Brilliant. "But there is a price using
hydroxyurea," he says. "Sometimes hydroxyurea works well, but oftentimes there
are many negative side effects.
"What we've discovered is a genetic 'switch' to turn the
embryonic form of beta-globin back on by turning the Sox6 protein off. So, we've
revealed a novel and key component of the switch. By tweaking that switch, we'll
be able to at least partially replace the damaged adult beta globin that sickle
cell anemia individuals suffer from," he says.
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