A Rare Lysosomal Storage Disease

Gene Therapy Halts Brain Disease in Two Boys

Gene Therapy Halts Brain Disease in Two Boys

By Jocelyn Kaiser
ScienceNOW Daily News
5 November 2009

Researchers have used a modified AIDS virus to halt a devastating brain disease in two young boys. The treatment, in which the virus delivered a therapeutic gene, marks the first time gene therapy has been successfully used against X-linked adrenoleukodystrophy (ALD)–a disorder that is always fatal if untreated. With this proof of principle, scientists hope versions of the AIDS virus engineered to carry different genes can now be applied to a variety of other diseases.

ALD is caused by a defect in an X chromosome gene that produces a protein called ALD. Cells need this transporter protein Gene Fixto break down certain fats; without it, the fats build up and damage the myelin sheathing that protects nerves. In X-linked ALD, which strikes mainly boys, patients develop neurological symptoms such as seizures and loss of vision around age 6 to 8, and within months they become paralyzed, deaf, and eventually die. In the 1980s, the parents of a boy with ALD developed a mixture of fatty acids they called Lorenzo's oil that may have delayed the disease in their son (and inspired a 1992 movie). But the only widely accepted way to stave off 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 sibling.

In search of an alternative, pediatrician Patrick Aubourg of INSERM in Paris, the French biomedical research agency, and the University Paris-Descartes, along with collaborators in France and Germany, tried gene therapy on two 7-year-olds with ALD who couldn't be matched with a bone marrow donor. They removed blood cells from each boy and treated the cells 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 the blood cells.

To provide the treated cells room to take hold and multiply, the researchers wiped out each patients' bone marrow with chemotherapy. Then they infused the repaired cells back into the patient, and the cells began cranking out ALD protein. The idea was that, after a few months, some of these cells would migrate into the brain.

As expected, parts of the patients' brains that already showed signs of myelin damage initially got worse after the gene therapy, because the modified cells did not migrate into the brain right away. But after 14 to 16 months, the boys' blood cells were still making ALD, and brain images showed that their disease had stabilized or improved, suggesting the protein was being produced there. One boy did worse on a non-verbal IQ test, and the other lost some vision, but their verbal test scores did not drop the way they do in patients who don't get any therapy. The results were comparable to a bone marrow transplant, the researchers report tomorrow in Science.

“It's a real milestone in the field,” says neurologist Florian Eichler of Massachusetts General Hospital in Boston. He cautions, however, that the therapy should not be attempted until a patient shows signs of ALD. That's because many boys with the defective gene do not develop the brain disease, and thus they should not be subjected to such a severe treatment regimen.

The study is also important because it suggests that a lentiviral vector may be safer than some other viruses used for gene therapy, says gene therapy researcher David Williams of Harvard Medical School and Children's Hospital Boston. In the best-known example, another viral vector cured about 20 patients with “bubble boy” immune disease, but it caused leukemia in several of them by inserting its DNA near a cancer gene. An analysis of the ALD patients' blood cells suggested the lentiviral vector is less likely to land in the wrong spot. Williams expects 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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Email response to this article from:

Cate Walsh Vockley, MS, CGC
Coordinator of Education, Referral and Advocacy
Niemann-Pick Disease Foundation
Senior Genetic Counselor
Medical Genetics
Children's Hospital of Pittsburgh

In addition, Karen Quandt, Vice-Chair of the NNDPF Board, asked Dr. Vanier about the studies and whether this technique can be applied to NPC. Dr. Vanier's response was as follows:

“Unfortunately the procedure described for adrenoleukodystroph y (ALD) is NOT applicable to NPC1 patients, because this strategy has a chance to work only in diseases where bone marrow or
cord blood transplantation has proven efficient. In ALD, bone marrow transplantation (BMT) has been shown quite efficient, provided it is done early enough. The big advance in the trial has been to use the patient's own cells, after correction by gene therapy. In NPC1 we know that bone marrow transplantation (BMT) has no effect on the neurological disease.

(Note that BMT has some chances to work in NPC2, although it is still too early to conclude in the one patient who survived the transplantation procedure).”


*This post does not reflect the views and opinions of Niemann-Pick Children’s Fund, Inc. This article is for informational purposes only. The sole credit of this article belongs to the author/website listed above.

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