March 25, 2004
Penn Researchers Identify Potential New Therapeutic
Approach for Sickle Cell Disease
(Philadelphia, PA) – University of Pennsylvania School of Medicine
researchers have identified an embryonic protein present
in all humans that, when produced in mice, dramatically
reduces symptoms of sickle cell disease. The discovery
raises the possibility of new treatment options for
sickle cell patients, say co-authors J. Eric
Russell, MD, Assistant Professor
of Medicine and Pediatrics, and Zhenning He,
research specialist, Department of Medicine. The research
appears in the April issue of Nature Medicine.
Sickle cell disease is an inherited, red-blood-cell
disorder in humans characterized by chronic anemia,
episodes of severe pain, and premature death. It is
caused by an error in one of the genes that produces
hemoglobin, an iron-protein component contained within
the red blood cells that carry oxygen to body tissues.
The defective gene directs production of abnormal hemoglobin,
resulting in deformed (sickle-shaped) red blood cells
that block small blood vessels. This results in pain,
stroke, heart attacks, kidney failure, and premature
death in adults and children.
Although there is no cure for sickle cell disease, treatments
are available, including administration of the anti-cancer
drug hydroxyurea, blood transfusions, and bone marrow
transplantation. Hydroxyurea is widely used to reactivate
the production of gamma globin, which substitutes for
the defective component of hemoglobin, called beta globin.
Although this approach does not cure the disease, it
frequently results in a lessening of symptoms.
Russell and He used a novel approach to modify alpha
globin, the other major component of hemoglobin. This
could help patients who have responded poorly to conventional
hydroxyurea treatment or who are unable to tolerate
its side effects. Conceivably, therapies resulting from
this study could be combined with standard treatments
to further reduce disease severity.
The researchers genetically engineered mice with sickle
cell disease to produce zeta globin, the embryonic form
of the human alpha chain of hemoglobin. Unlike mice
with sickle cell disease, the genetically altered mice
had normal blood counts and were no longer anemic. In
addition, the life span of their red blood cells was
extended almost five-fold to normal levels. Sickled
cells did not appear in the blood of the mice and kidney
“Our work demonstrates a novel therapeutic approach
that reverses the disease process in mice with sickle
cell disease,” says Russell. “Clearly, there
is much more work to be done before this approach can
be tested in humans. Nevertheless, targeted reactivation
of zeta globin, either alone or in combination with
existing treatments, anticipates therapies in humans
that are more flexible and potentially more effective
than those that are currently available for this devastating
Sickle cell disease affects millions of people throughout
the world. It is the most common inherited genetic disease
in the United States, affecting approximately 72,000
people. The disease occurs in about one in every 500
African-American births and about one in every 1,000-1,400
Hispanic American births.
Additionally, approximately two million Americans, including
1 in 12 African Americans, have sickle cell trait. They
do not suffer from the disease itself, but have the
potential to pass the disease on to their children.
The research was supported in part by grants from the
National Institutes of Health. The authors have no competing
financial interests in this research. Dr. Russell can
be reached at 215-590-3880 or firstname.lastname@example.org.
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