Gene therapy against a rare brain disease

Maxim Rousseau, Polit.<url> based on the materials of Science: Gene therapy stops rare childhood brain disease

At the annual conference of the American Society for Gene and Cell Therapy, a report was made on the successful use of gene therapy for the treatment of a rare genetic brain disease – adrenoleukodystrophy. Sixteen of the seventeen boys who participated in the experiment remain relatively healthy for two years after a specially engineered virus brought into their cells the gene needed to produce the protein needed by their body.

This disease develops due to a mutation in one of the genes that determine the processing of fatty acids in the body. As a result, the enzyme responsible for their cleavage does not perform its functions enough, and these substances accumulate in the adrenal glands and the "white matter" of the brain – long processes of nerve cells. Fatty acids cause the loss of myelin, which forms the sheath of nerve fibers.

The brain of a patient with adrenoleukodystrophy. The white areas are those where myelin is lost.
Frank Gaillard/Creative Commons

Since the disease is caused by a mutation in the X chromosome, it manifests itself in boys, in whose genome the X chromosome is one and its defect is not compensated by anything. Women who have two X chromosomes can remain healthy if at least one of them has the right gene functioning normally. But they will still pass the mutation on to their offspring.

Adrenoleukodystrophy occurs in approximately one in 21,000 boys. It manifests itself in cognitive disorders, visual and hearing disorders, coordination disorders. Symptoms gradually increase, and most patients die before the age of 12.

At the moment, the only means that partially helps patients is bone marrow transplantation. Leukocytes from the transplant enter the brain, where they turn into glial cells that produce the necessary enzyme. However, bone marrow transplantation is a complex and difficult procedure for the patient with a high risk of immune rejection, besides in this case it is still necessary to find a suitable donor.

In the late 2000s, French doctors proposed a new method of therapy. They infected the cells of two patients with a modified virus that contained the desired gene. As the authors of the study reported in 2009 in the journal Science, this method stopped the development of the disease.

Now scientists have tested a similar therapy in a larger study under the auspices of the biotech company Bluebird Bio. Since the disease is very rare, the trial was conducted in seven hospitals in five countries. The researchers took blood cells from 17 boys aged 4 to 13 years, suffering from adrenoleukodystrophy. Then the cells were treated with a modified HIV virus, where a gene encoding a missing protein in the patients' body was inserted. Then they returned the modified cells to the patients' bodies. According to David Williams from Harvard University, within six months, the condition of 16 patients has stabilized.

A study of the brains of these patients, conducted two years later, found that most of them had no signs of inflammation or loss of myelin. In 16 patients, there are no characteristic symptoms of the disease: loss of vision or difficulty walking.

David Williams emphasized that none of the patients participating in the experiment had a case of inserting a gene by a virus into the wrong place of the genome. In early gene therapy experiments, this sometimes happened and led to uncontrolled cell growth and cases of leukemia. In the current study, only one case of bladder infection and one case of cardiac arrhythmias were noted among the complications, both patients were successfully cured.

The boys who underwent therapy did not become completely healthy. The disease can return after there are no modified cells left in the body carrying a serviceable gene. Then they will need to re-transplant their own genetically modified cells or bone marrow transplantation. But so far they all go to school and live a normal life.

After two years have passed for all patients from the date of treatment, Bluebird Bio intends to apply to the Food and Drug Administration (FDA) with a request to allow the use of this method of therapy in the United States. Although in European countries regulatory authorities have already begun to issue permits for the treatment of rare diseases with the help of genome modification, in the United States, no gene therapy method has yet received official approval.

Portal "Eternal youth" http://vechnayamolodost.ru  12.05.2016