Genetics and stem cells

Lorenzo's oil disease gene trial

The genetic brain disease that was portrayed in the film Lorenzo’s Oil “has been stopped in its tracks by a gene therapy”, according to The Times.

This rare but fatal disease, called adrenoleukodystrophy (ALD), is caused by a mutation in a gene. Although the disease can be treated by bone marrow transplant, this requires a suitable bone marrow donor to be found. The study used experimental gene therapy in two seven-year-old boys with ALD who did not have donors. A working copy of the faulty gene was inserted into the boys’ cells to try to improve their condition. The boys continued to develop areas of brain damage for a year, after which they had no further brain damage or decline in brain function. The boys are now aged nine and 10.

This initial human study illustrates the potential of gene therapy for treating ALD. As yet, it is not known what the longer-term outcome of the gene therapy will be, or what effects it may have in adults with ALD.

Where did the story come from?

This research was conducted by Dr Nathalie Cartier and colleagues from University Paris-Descartes and other centres in France and the US. No specific sources of funding for the study were reported, but the researchers were supported by the INSERM research foundation and other charitable foundations, government bodies and companies. The paper was published in the peer-reviewed journal Science.

The study was reported in The Times, which provided a good account of the research.

What kind of research was this?

This was a case series which looked at the effects of gene therapy in boys with ALD, a disease caused by mutations in a gene called the ABCD1 gene. This gene lies on the X chromosome. Because boys only have one X chromosome in each cell, they only have one copy of this gene, rather than two found in girls. If this single copy of the gene in boys is mutated, they have no 'back-up' copy for the body to use. Therefore, ALD affects boys more than girls.

Without a working copy of the ABCD1 gene, boys with ALD experience 'demyelination', a process were they gradually lose myelin, the fatty insulating material around nerves. This results in brain damage and eventually death. The disease is rare, affecting around five boys in 100,000.

One potential method of treating ALD is gene therapy, an experimental process in which normal genes are introduced into the body in the hope that they will replace faulty ones. Initial trials of gene therapy on cells and in mouse models of ALD had been promising, so in this next phase of research the scientists wanted to carry out the first gene therapy for ALD in humans.

As this was a new therapy for a rare disease, the researchers included just two boys in the study, which aimed to explore the effects of the gene therapy. If the therapy could be shown to be acceptably safe and beneficial in these boys, it could lead to further studies to test the therapy in more patients with different types of disease. Future studies will also be needed to determine how well the therapy compares to stem-cell transplant, an ALD treatment currently used in boys who have a matched bone marrow donor.

What did the research involve?

The researchers identified two boys with ALD who did not have matched donors for bone marrow transplant. The boys were both aged seven and showed signs of progressive myelin loss in their brains.

The researchers took blood from these boys and isolated the cells that have the potential to generate new blood cells. They then exposed these cells to a virus that had been genetically engineered to be harmless, but which could introduce a working copy of the ALD gene into cells. The boys were given chemotherapy to destroy the remaining blood-producing cells in their bodies before the genetically engineered cells were introduced back into their bloodstream.

The researchers monitored the boys to see when their bodies would start to produce new blood cells, and if these blood cells were producing ALD. They also carried out brain scans and monitored the boys’ cognitive performance and muscle function.

What were the basic results?

The researchers found that the boys’ bodies started producing new blood cells 13 to 15 days after the transplant. Thirty days after the transplant, about a quarter of the boys’ white blood cells were producing ALD. This decreased over time, with about 10-15% of the cells producing ALD at 24-30 months after the transplant.

Boy one
Inflammation that had surrounded areas of demyelination in his brain disappeared on brain scanning a year after the transplant. The demyelination itself continued to spread in his brain for up to 14 months after the transplant, after which it stopped. The boy’s verbal intelligence remained unchanged compared to his performance in cognitive tests before gene therapy. Although there was an initial decline in his nonverbal performance, his performance stabilised. Seven months after the transplant, he developed muscle weakness on the right side of his body, but this improved and was nearly back to normal by month 14.

Boy two
Brain scanning nine months after the transplant showed that inflammation had also disappeared, although some inflammation briefly reoccurred at 16 months. Demyelination was still spreading in his brain until 16 months after the transplant, after which it stopped. Brain scans suggested that demyelination had been reversed in one area of the brain, which does not happen in untreated ALD. The boy’s muscle and cognitive function remained stable and did not worsen after gene therapy, except for a problem with vision that appeared 14 months after the transplant.

How did the researchers interpret the results?

The researchers say that what they observed in the boys’ brains is “in sharp contrast with the continuous progression of cerebral demyelination in untreated ALD patients”, but was similar to what is typically observed after donor transplant.

The authors also say that their results support the case for further testing of this form of gene therapy in patients who have ALD with brain demyelination and no matched donors. This research should include adult ALD patients. They say that they will need longer follow-up and a larger sample of treated patients to ensure that any risks associated with gene therapy are minimal.


This research indicates the potential of gene therapy in ALD. The study is important as, although the disease is rare, its effects are serious and fatal if not treated. The boys have been followed for about 30 months and the longer-term effects of the treatment are not yet clear. As the authors note, larger studies with longer follow-up are needed to determine the longer-term effects of this treatment and any risks associated with it. Further studies are also needed to determine how well the therapy compares to stem-cell transplant in boys who have a matched donor.

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