Zinc fingers against Hunter Syndrome
Genomic editing was tested for the first time on a living person
Anna Kaznadzei, N+1
American scientists have for the first time tested the technique of gene editing directly in the body of a living adult suffering from an incurable genetic disease. The success of the treatment can be judged in about two months, when it becomes clear whether the genetic breakdown has been "repaired" at least in part of the cells, the Associated Press reports. Additional details can be found in the press release of UCSF Benioff Children's Hospital Oakland.
The patient whose genome has been edited is named Brian Maddox. He suffers from Hunter syndrome, a rare disease associated with the X chromosome. It is inherited recessively, that is, both parents must have the defective gene. One of the enzymes, iduronate—2-sulfatase, is not synthesized in the liver cells of patients, and therefore the cleavage of glucosaminoglucans, substances that bind cells in tissues, is disrupted. As a result, they accumulate in the body and are not updated in time, which affects a variety of organs and tissues. Signs of the disease appear already in the second year of life. People with Hunter syndrome tend to have distorted, "rough" facial features and a large head. The disease affects the nervous system and thinking, can be associated with autism, hyperactivity and obsessive-compulsive disorder. Patients often have obstruction of the upper respiratory tract, rhinitis, inguinal and umbilical hernias and other symptoms.
It is currently impossible to cure Hunter syndrome, patients are treated symptomatically — with weekly infusions of an artificial analogue of the enzyme, and sometimes with bone marrow transplants. Treatment with an artificial enzyme costs more than 100 thousand dollars a year, and does not improve, for example, the symptoms of the nervous system.
Doctors from the Auckland Children's Hospital worked with Maddox under the direction of Paul Harmatz. He is 44 years old, which, unfortunately, is unusual for patients with Hunter syndrome — a significant part of them die in childhood (now only about two thousand patients are registered worldwide). During his life, he underwent 26 operations to remove hernias, bone sprouting into the spinal cord, as well as surgical interventions on the eyes, ears and gallbladder. Every week he needs an infusion of an artificial enzyme, while such injections do not cure him of all manifestations of the disease.
Maddox agreed to become the first patient in the world whose genes were edited directly in his body, and not in cells grown separately or simply previously extracted from his body (we recently told, for example, about a boy with epidermolysis bullosa who had a new transgenic skin grown).
A copy of the working gene encoding the enzyme was injected into Maddox using Zinc finger nuclease technology (one of the modern methods of genomic editing, which is now used along with the more well-known CRISPR technology). At the same time, neutralized viral particles carrying a coded gene editing tool enter the body using a conventional intravenous drip. Then, with the blood flow, they are sent to the liver cells, where the instrument is first synthesized and then begins to work. Specially designed proteins with zinc fingers (structural components stabilized with zinc ions) recognize a given DNA sequence and cut it in this section (in this case, the gene is inserted into the region of the gene encoding the albumin protein). Then a copy of the working iduronate-2-sulfatase gene is inserted there, and the DNA is cross-linked again.
Doctors note that in order for the body to produce a sufficient amount of the enzyme, it is necessary that at least one percent of liver cells have the "correct" copy of the gene.
Gene therapy may be associated with certain negative consequences. So, sometimes the immune system reacts too strongly to the introduced viral particles (at the moment they are already designed in such a way that this should not happen). In addition, it is important where exactly the new gene gets, because embedding something in some parts of the genome can affect genes associated with cancer. However, in this case, as in CRISPR technologies, the place of editing is set with a fairly high degree of accuracy. In addition, the target of this therapy is only the liver — scientists separately note that it should not affect other organs and tissues, since the viral particles used are able to penetrate only into liver cells. Experiments conducted with animals have yielded positive results.
It will be possible to say whether the new gene has "taken root" in at least a month. Maddox is aware that therapy may not work; in addition, at his age, many changes in the body are already irreversible. However, according to him, he has been waiting for the possibility of genome editing for the last 15 years, and now it is a great honor for him to participate in such an unprecedented experiment. He hopes that his experience, in any case, will benefit other patients, and with positive results will deprive him of the need to receive injections of an expensive artificial enzyme every week.
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