Gene Therapy Used to Treat Sickle Cell Disease in Mice

Bijal P. Trivedi
National Geographic Today
December 13, 2001
Researchers have successfully used gene therapy to treat sickle cell
disease in mice.

The researchers, led by Philippe Leboulch,of Harvard MedicalSchool and the Massachusetts Institute of Technology, designed a new
gene that can counter the effects of the sickle cell gene.

Sickle cell disease, which can be fatal, is caused by a genetic mutation in the
hemoglobin gene that causes red blood cells to become crescent or
sickle-shaped and sticky.

Inheriting two bad copies of the gene—one from each parent—leads to fragile, sticky red blood cells that clump together and can block blood vessels leading to strokes and damaging organs.

A person with one mutated copy sickle cell gene does not show any symptoms of the disease and does not require treatment. In fact, having one copy of the mutant gene is common in tropical countries where malaria is endemic because it actually protects against malaria; it is fairly common in people of African, Indian, Mediterranean and Middle Eastern descent.

About 1 in 13 African Americans carries one sickle cell gene. About 72,000 in the United States have two copies of the sickle cell gene and have the disease.

Leboulch's team removed the bone marrow from mice with a sickle cell disease, isolated the stem cells—which give rise to red blood cells—and inserted the new anti-sickling gene. When the genetically modified stem cells were transplanted back into the mice, they produced healthy round red blood cells.

Although the mutant gene is still present in the stem cells, the new gene is able to counteract its ill-effects and produce healthy cells, says collaborator Ronald Dorazio, of Genetix Pharmaceuticals in Cambridge, Massachusetts.

One of the greatest difficulties faced by the gene therapy researchers is getting the therapeutic gene into enough cells to actually make a difference.

Leboulch overcame this issue by using a modified version of HIV to transport the "anti-sickle" gene into the stem cells. The segments of HIV Leboulch used allow the virus to deliver the therapeutic gene to many more bone marrow stem cells.

Ten months after receiving the modified stem cells, about 99 percent of the red blood cells in the mice contain the anti-sickling gene and appear healthy.

The study is published in the December 14th issue of the journal Science.

Although human clinical trials are at least two years away, the scientists feel the results of the new study may eventually lead to therapies for the human form of the disease. The researchers must first prove that the HIV-like virus is safe for humans and find a way of getting rid of stem cells that do not receive the therapeutic gene.

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