Scientists have cured the painful blood disorder sickle cell anemia in mice using gene therapy. The feat offers promise of an eventual cure for a disease prevalent in Africa, the Middle East, Mediterranean countries, India and many Spanish-speaking parts of the world.
The goal of gene therapy is to replace faulty copies of genes that cause a disease with healthy versions that cure it. Genes are the molecules in cells that determine our physical processes.
In the case of sickle cell anemia, two copies of a mutant gene are required to cause the disease, one from each parent. In a person with both copies, red blood cells containing hemoglobin, which carry oxygen to all parts of the body, are bent into a rigid sickle shape. They clump together and block tiny blood vessels, causing severe pain and damaging organs by depriving them of oxygen.
A U.S. team led by Harvard Medical School researcher Philippe Leboulch has corrected the disorder in mice by replacing the gene that causes the red blood cells to bend.
"The gene product is now preventing the abnormal hemoglobin that causes those red blood cells to be distorting their shapes and to occlude vessels in various organs," he explains. "So all the signs of the disease as far as we could tell in those sickle cell mice were prevented from happening."
The Leboulch group reports in the journal Science that in two types of mice bred to have sickle cell disease, the gene therapy eliminated the bent red blood cells in one group and reduced their occurrence eight-fold in the other.
The corrective gene the scientists used to do this was not the normal hemoglobin gene found in nature. Instead, they manipulated it to add parts of another blood cell gene known to counter the sickle shape.
They then attached this engineered gene to a safe fragment of the HIV virus. Viruses, especially HIV, are effective tools for delivering genes into cells. After all, they insert their own disease genes into cells efficiently, so they have become the delivery device of choice for gene therapy.
Next, the Leboulch team mixed this gene-virus product with samples of the animals' bone marrow, the tissue where blood cells are produced. The HIV fragment infected the bone marrow with the healthy hemoglobin gene. The researchers reinjected the bone marrow back into the animals after irradiating them to kill their bad marrow, and the altered bone marrow cells began producing normal red blood cells.
Last year, physician Michel Sadelain of Memorial Sloan-Kettering Cancer Center in New York used this technique to cure mice of a related but milder blood disorder called thalassemia.
"Now this study in Science shows us that that strategy can be extended to the other major congenital anemia, sickle cell disease," says Dr. Sadelain. "So in a similar strategy, this group has now shown that a treatment can be achieved in mice with sickle cell disease, and this is very exciting."
The technique is far from ready for people, however. Philippe Leboulch says he wants to be sure the HIV fragment used for gene delivery is absolutely safe for humans.
He also would like to destroy the damaging bone marrow in people by a gentler method than radiation. He suggests using drugs known to kill cells. By attaching a drug resistance gene to the cells in the treated bone marrow, they could survive the drug.
Mr. Leboulch says it is important for the treated bone marrow to overtake the function of the untreated tissue.
"If you have bone marrow cells that have not been corrected and you mix that with bone marrow cells that now have been treated, there would be a competition between them and you would not succeed in having close to perfect reconstitution of the marrow with only treated cells," he says.
The next step in this research is to test the therapy in monkeys, an animal genetically closer to humans than mice.