Gene fix. The blood cell with red dots was designed to ADL, a protein that was missing in this patient until he received the gene therapy 2 years earlier.
Patrick Aubourg
The researchers used a modified AIDS virus to stop a devastating brain disease in two young boys. The treatment, in which the virus has issued a therapeutic gene is the first time gene therapy has been used successfully against adrenoleukodystrophy X-linked (ALD) - a disorder that is always fatal if untreated. With this proof of principle, scientists hope versions of the AIDS virus designed to carry different genes can now be applied to a variety of other diseases.
ALD is caused by a defect in a gene on the X chromosome that produces a protein called ALD. Cells need this transporter protein to break down certain fats; without it, the fats accumulate and damage the myelin sheath that protects nerves. In X-linked ALD, which strikes mainly boys, patients develop neurological symptoms such as seizures and vision loss around 6 to 8 years, and in a few months, they become paralyzed, deaf, and eventually die. In the 1980s, the parents of a boy with ALD developed a fatty acid mixture they called Lorenzo's oil that may have delayed the disease in their son (and inspired a 1992 film). But the only way to ward widely accepted ALD is a bone marrow transplant, which is risky - 20% to 30% of patients die or have serious complications -. And works best if the donor marrow comes from a brother
Seeking an alternative, pediatrician Patrick Aubourg of INSERM in Paris, the French biomedical research agency, and the University of Paris -Descartes and collaborators in France and Germany tried gene therapy on two 7 years with ALD who could not be associated with a bone marrow donor. They removed the child's blood cells and cells treated with a so-called lentiviral vector, a modified HIV virus carrying the gene for the enzyme they lacked. The virus could not replicate, but it stitched the gene into the DNA of blood cells.
To provide the cells treated room to enter and multiply, the researchers destroyed each bone marrow of patients with chemotherapy. Then they infused the repaired cells in the patient, the cells began to turn the crank on the ALD protein. The idea was that after a few months, some of these cells could migrate in the brain.
As expected, the parts of the brain of patients who have already shown signs of myelin damage initially worsened after gene therapy, because the modified cells will migrate into the brain immediately. But after 14 to 16 months, the blood cells of the boys were still making ALD, and brain images showed that the disease had stabilized or improved, suggesting the protein was produced there. One boy did worse on a nonverbal IQ test, and the other has lost vision, but their scores on verbal tests did not drop as they do in patients not receiving therapy. The results were similar to a bone marrow transplant, the researchers report tomorrow Science .
"There is a real milestone in the field," says neurologist Florian Eichler of Massachusetts General Hospital in Boston. However, it warns that the treatment should not be attempted until the patient has signs of ALD. This is because many boys with the defective gene do not develop the brain disease, and therefore they should not be subjected to such harsh treatment regimen.
the study is also important because it suggests that a lentiviral vector can be safer than other viruses used for gene therapy, gene therapy, says researcher David Williams of Harvard Medical School and Boston children's Hospital . in the best known example, another viral vector cured 20 patients with "bubble boy" immune disease, but it caused leukemia in several of them by inserting its DNA near a gene cancer . An analysis of blood cells of ALD patients suggested that the lentiviral vector is less likely to land in the wrong place. Williams expected that lentiviral vectors will now be used to treat other genetic diseases that involve blood cells, such as sickle cell disease.
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