Sickle Cell Cured in Mice

Human studies 'in two to three years'

THURSDAY, Dec. 13, 2001 (HealthDayNews) -- Gene therapy has cured sickle cell disease in mice, say a team of researchers who are now planning for the first human trial of their method.

The researchers used radiation and a drastically modified version of HIV, the virus that causes AIDS, in their successful attempt to wipe out the incurable blood disease in an animal model.

"Our next step is to repeat the experiment in human-derived cells and also in primate models to see if higher animals respond in the same way the mice did," says Dr. Ronald L. Nagel, lead author of a paper reporting the result in the journal Science. "After that, we will be ready for clinical trials [on people], which we estimate will take place in two to three years."

Sickle cell disease gets its name from the abnormal scythe-like shape of the red blood cells in people who carry a mutated form of the gene for beta globin, a building block of hemoglobin. An estimated 1 in 13 black Americans carries one sickle cell gene; the disease occurs when someone inherits two of these mutated genes.

The distorted red cells get stuck in blood vessels, causing pain, anemia, stroke and organ damage, and weakening resistance to infection. The treatment centers on supportive therapy; there is no cure.

Nagel, a professor of medicine at Albert Einstein College of Medicine in the Bronx, says the challenge has been to get the normal beta globin gene, a large gene, into the bone marrow cells that produce red blood cells. Previous attempts using the library of viruses developed as delivery agents for gene therapy produced only minimal results, he adds.

The HIV delivery method was developed by team member Dr. Phillippe Leboulch, an assistant professor of medicine at Harvard Medical School. The technique was used in animal models of sickle cell disease that were developed by Nagel.

In their tests, the abnormal bone marrow of the mice was eliminated by radiation, and the beta globin gene was then delivered to the marrow-producing stem cells.

In one animal trial, there was an eightfold reduction in the number of abnormal red cells; in another trial, all the abnormal cells were eliminated, Leboulch says.

He calls it "a solid first step toward helping people who suffer from sickle cell disorders."

But the method does need some work, he adds. It is desirable "to devise milder ways to rid the body of existing bone marrow without toxic radiation," he says.

Such methods are available, Nagel says.

"There are other alternatives, such as drugs," he says. "There also are other methods to enhance the abilities of the transplanted cells."

The use of the modified HIV virus should not arouse concern, he adds. "All the guts of HIV have been eliminated, and there is no evidence that this is a dangerous virus. The vector form that we use is definitely not infectious."

The researchers looked to HIV to create the delivery system because the virus has a proven track record for infiltrating such cells as blood-forming stem cells in the marrow.

Nagel says he is confident that gene therapy for sickle cell disease will become available sooner or later.

"The likelihood of success is high because there are so many laboratories working on this," he says. "Someone will come up with the right thing."

The sickle cell gene is most common in people from Africa and the Mediterranean region because it confers some protection against malaria, which is historically endemic to those areas.

What To Do

Gene therapy offers no immediate help for people with sickle cell disease, but this research may pave the way for some kind of treatment.

Information about sickle cell disease and what can be done about it is available from the National Heart Lung and Blood Institute, part of the federal National Institutes of Health, which helps fund gene therapy research.

Emory University also has an extensive site devoted to sickle cell anemia.

SOURCES: Interviews with Ronald L. Nagel, M.D., professor of medicine, Albert Einstein College of Medicine, Bronx, N.Y.; Phillippe Leboulch, M.D., assistant professor of medicine, Harvard Medical School; Dec. 14, 2001, Science
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