Repetition of the passed
Gene therapy and rare liver disease
Maxim Rousseau, Polit.roo
A new method of gene therapy has proved to be an effective remedy for a rare genetic disease – ornithine transcarbamylase deficiency, which leads to liver damage. The report on the ongoing clinical trial was presented at the conference of the American Society for Gene and Cell Therapy.
Ornithine transcarbamylase is an enzyme involved in the cycle of processing excess nitrogen into urea in the human body, it works in the liver and is responsible for the conversion of carbamoyl phosphate and ornithine into citrulline. A mutation in the gene encoding this enzyme leads to disruption of its work, which causes a dangerous increase in ammonia levels. The gene is inherited recessively and is located on the X chromosome, which means that men suffer more than women who have two X chromosomes. The disease occurs in about one person out of fifty thousand. In boys, it often ends in death shortly after birth. High levels of ammonia mainly cause brain damage. After birth, the baby looks normal, but by the second day of life it becomes irritable, sluggish and stops eating. Convulsions may begin, metabolic encephalopathy develops without urgent intervention, which can progress to coma and death during the first week of life.
Girls who have one functional copy of the gene, as well as boys with mutation variants that allow the enzyme to at least partially preserve its functions, can survive by following a low-protein diet and taking medications. These patients often experience headaches, nausea, vomiting, delirium, erratic behavior or seizures.
At the moment, the only method that allows to cure the disease is a donor liver transplant. Of the 51 patients with over-the-counter drug deficiency who underwent liver transplantation, in 2005 the five-year survival rate was more than 90%. In severe cases of the disease, in order to save the child, liver transplantation has to be resorted to at six months. But even with timely detection and treatment, most patients in the neonatal period have severe neurological and intellectual disabilities. Liver transplantation cannot cure brain damage that has already occurred from ammonia poisoning, but it prevents future episodes of hyperammonemia and stops further damage.
Twenty-two years ago, ornithine transcarbamylase deficiency became one of the first genetic diseases for which a gene therapy method was developed. But the work was stopped after the unexpected death of one of the participants in the experiment. Eighteen years old Jesse Gelsinger, with a mild form of the disease, volunteered to participate in a study conducted at the University of Pennsylvania. He received an injection of a modified adenovirus that was supposed to deliver the normal ornithine transcarbamylase gene to liver cells. But suddenly the virus caused a strong immune reaction and organ failure. The patient died four days later, becoming the first person in history to die during a clinical trial of gene therapy. Federal regulators found that the head of the study, gene therapist James Wilson, violated the rules, including ignoring serious side effects in other subjects. The university paid a fine of $500,000. The government banned Wilson from participating in human clinical trials for five years. All gene therapy research in the US has been halted, and pharmaceutical companies have stopped supporting such projects.
After this incident, Wilson's laboratory moved on to work with safer adenoassociated viruses, it was this variant of carriers of therapeutic genes that allowed to revive research in the field of gene therapy. Such viruses have been used in more than 250 studies and two gene therapy methods that have been approved for clinical use in the United States. After that, James Wilson decided to return to the problem of ornithine transcarbamylase deficiency and conducted the first trials of adenoassociated viruses with a therapeutic gene in mice. After their successful completion, human trials sponsored by Ultragenyx were initiated. Although the therapy helped eleven study participants to varying degrees, within one year, two men and one woman had normal urea levels, and they no longer needed a special diet or medication. Three "partially responding" participants reduced the number of medications and dietary restrictions by at least half.
Paul Gelsinger, the father of the deceased patient, who followed the progress of the current trial, commented on its results as follows: "I think it's great that Ultragenyx has the courage to take on ornithine transcarbamylase deficiency… I also think it's wonderful that they have achieved efficiency, even limited."
Ultragenyx plans to launch the third phase of the trial later this year. However, for infants with a severe form of the disease, therapy will only be a temporary solution, which may help them gain time for a liver transplant, because as the child grows, dividing liver cells will gradually lose DNA with the normal version of the gene. Therefore, Wilson's laboratory is now developing a new method based on CRISPR genome editing. It will allow you to correct a malicious mutation directly in the patient's body. But this method is currently being tested only on mice.
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