Sickle Cell Success

Researchers have cured laboratory mice of sickle cell anemia, the inherited blood disorder that affects more than 70,000 Americans, in an experiment using stem cells, genes and a modified HIV virus.

Although the treatment is years away from being tested on humans, experts called the experiment a milestone.

"It corrected the sickling problem throughout the bodies of these mice," said Philippe Leboulch, a Harvard Medical School and Massachusetts Institute of Technology scientist who led the research team. "All of the mice were cured permanently."

Leboulch said additional study is needed before the technique can be tried on humans and the first clinical trial could come in about two years. A report on the study appears Friday in the journal Science.

The disease causes intense pain. It damages the liver, lungs and kidneys and can trigger stroke or infections. There is no cure in humans, and treatment consists of combating the symptoms with antibiotics, blood transfusions and surgery. A drug, called hydroxyurea, helps control some symptoms in adults, but it has not been approved for children.

About 1.2 million Americans carry one sickle cell gene. They are said to have the sickle cell trait and are not affected by the disease. A person must inherit two sickle cell genes - one from each parent - to have the disease. A child born to two parents with the sickle cell trait has one chance in four of inheriting the disease.

Sickle cell anemia is most common in people of African heritage. It also is found in people of Greek, Indian and Italian origin and can occur in any race.

"Although much more research is needed before human application, this is a significant achievement that brings us closer to human gene therapy for what is a very serious genetic blood disorder," said Dr. Claude Lenfant, director of the National Heart, Lung and Blood Institute, one of the National Institutes of Health.

"This is an exciting result," said Dr. Michel Sadelain of the Memorial Sloan-Kettering Cancer Center in New York. "It is an important milestone in gene therapy."

Sadelain earlier achieved a similar success in mice by correcting the genetic flaw that causes thalassemia, a blood disorder related to sickle cell anemia.

In the new study, researchers used two types of mice that are bred to have a blood disease closely resembling the sickle cell anemia disease in humans.

They removed from the mice samples of the bone marrow, which makes blood, and then irradiated the mice to kill the remaining abnormal bone marrow.

The researchers mixed with the removed bone marrow a fragment of the HIV virus that had been manipulated to contain a normal red blood cell gene. The virus infected the bone marrow, carrying into the blood-making cells the normal red blood cell gene. The bone marrow was then re-injected into the mice.

Once in the animals, the genetically altered bone marrow cells produced normal red blood cells and corrected the sickling diseas.

After 10 months, the mice were killed and their organs and blood examined.

Leboulch said there was no evidence of abnormal blood nor of the organ damage that is common with sickle cell anemia.

The gene therapy technique will not be tried in humans, said Leboulch, until the researchers learn how to safely neutralize the abnormal blood-making gene in patients. Radiation was used in the mouse experiment to kill the animal's bone marrow, but this would not be appropriate for human sickle cell disease patients, said Leboulch.

Greg Evans of the NHLBI said that research is under way to find a safe way to partially destroy the abnormal bone marrow in patients. The technique would then make room for the genetically corrected bone marrow.

Sadelain said that earlier studies showed that the genetically corrected bone marrow is ineffective against the blood disorder unless most of the abnormal bone marrow is neutralized.

Both sickle cell anemia and thalassemia are caused by a failure of a gene that helps to make hemoglobin, the protein in red blood cells that carries oxygen.

In thalassemia, the gene fails to make enough hemoglobin.

In sickle cell disease, the gene makes an abnormal hemoglobin that is sticky and stiff. Instead of the soft, doughnut-shaped, normal hemoglobin, the abnormal protein often forms into a distinctive sickle shape with a sharp point. The abnormal hemoglobin tends to clog small vessels, blocking the flow of blood. This starves tissues of oxygen and can cause damage throughout the body.

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