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In the brain of an ALD patient, white areas have lost the myelin that protects nerves.

In the brain of an ALD patient, white areas have lost the myelin that protects nerves.

Frank Gaillard/Creative Commons

Gene therapy stops rare childhood brain disease

Gene therapy is living up to its promise of halting a rare, deadly brain disease in young boys. In a new study presented in Washington, D.C., yesterday at the annual meeting of the American Society of Gene and Cell Therapy, all but one of 17 boys with adrenoleukodystrophy (ALD) remained relatively healthy for up to 2 years after having an engineered virus deliver into their cells a gene to replenish a missing protein needed by the brain. The results, which expand on an earlier pilot study, bring this ALD therapy one step closer to the clinic.

About one in 21,000 boys are born with ALD, which is caused by a flaw in a gene on the X chromosome that prevents cells from making a protein that the cells need to process certain fats—females have a backup copy of the gene on their second X chromosome. Without that protein, the fats build up and gradually destroy myelin sheaths that protect nerves in the brain. In the cerebral form of ALD, which begins in childhood, patients quickly lose vision and mobility, usually dying by age 12. The disease achieved some degree of fame with the 1992 film Lorenzo’s Oil, inspired by a family’s struggle to prolong their son’s life with a homemade remedy.

The only currently approved treatment for ALD is a bone marrow transplant -- white blood cells in the marrow go to the brain and turn into glial cells that produce normal ALD proteins. But bone marrow transplants carry many risks, including immune rejection, and matching donors can’t always be found. As an alternative, in the late 2000s, French researchers treated the bone cells of two boys with a modified virus carrying the ALD gene. They reported in Science in 2009 that this halted progression of the disease.

Now, researchers have tested a similar therapy in a larger trial sponsored by the biotech company Bluebird Bio. The scientists removed blood cells from 17 boys with cerebral ALD ranging from age 4 to 13 and treated the cells with a modified HIV virus carrying the gene for the ALD protein. They then reinfused the cells back into patients. Within 6 months, 16 patients stabilized, reported David Williams of the Harvard University–affiliated Dana-Farber Cancer Institute and Boston Children’s Hospital. In brain scans taken up to 2 years later, most had no further signs of inflammation or loss of myelin. And 16 of the 17 had no signs of neurological decline such as vision loss or trouble walking.

Williams called the results “very exciting.” None of the patients showed signs that the gene had inserted into the wrong place on the genome and triggered uncontrolled growth of some cells—a problem that led to leukemia in some patients in an earlier gene therapy trial. (One patient in the ALD study had a bladder infection and another an irregular heartbeat that may have been related to the therapy, but both recovered.)

The boys aren’t completely healthy. Gene therapy doesn’t reverse ALD, and the disease can progress in the few months after treatment that it takes for the modified cells to turn into glial cells and make the ALD protein. But they are in school and living normal lives. “The key is to transplant early,” soon after a child is diagnosed with ALD, Williams says.

The results are "very impressive," says gene therapy researcher Cynthia Dunbar of the National Heart, Lung, and Blood Institute in Bethesda, Maryland. She notes that the study is also a huge logistical achievement—because ALD is so rare, the trial took place at seven sites in five countries, where each patient’s genetically modified cells were carefully shipped from a central manufacturing site.

Bluebird needs to wait until all the patients are 2 years out of treatment before applying to the U.S. Food and Drug Administration (FDA) for regulatory approval. Although European authorities have already given the nod to a gene therapy for a rare disorder and are expected to soon approve a second, FDA has yet to approve a single gene therapy.