New therapeutic approach for sickle cell disease

03/30/04

(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 function normalized.

"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 condition."

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.

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