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Elena Foer, "The Attic" 

Genetic editing began to be seriously discussed relatively recently, but today it is successfully used to treat patients, and those who cannot be helped otherwise. The Attic explains in detail what genome editing is and when it will become a daily practice in hospitals and polyclinics. 

The human genome contains about 20-25 thousand active (i.e. protein-coding) genes. Scientists have already linked mutations in three thousand of them with various diseases, and work in this area continues. These figures are perhaps the simplest explanation for why treatment with genome editing is causing distinct enthusiasm in scientific and medical circles. 

Genetic editing specialists "edit" DNA with the help of "genetic scissors" – enzymes called nucleases. They break DNA strands in predetermined places, and the cut fragment can then be removed, edited or completely replaced with a new one made "in vitro".

Today there are two most effective technologies of genetic editing. The first allows you to deliver to the cells the DNA sections necessary to restore the function of your own gene, the "breakdown" of which led to the development of the disease. With the help of the second one, it is possible to suppress the activity of defective genes by blocking RNA, which reads the information recorded in them and becomes the main one for the subsequent construction of proteins. And if there are no proteins, then we can say that the gene is "off". 

And although both technologies are not universal, stories of successful cases of their clinical application have already begun to appear. Moreover, these are stories of healing of those patients who had no hope of recovering with the help of other methods.

The first patients were 12 carriers of HIV infection from the USA. 

The immunodeficiency virus penetrates into human blood cells, namely T-lymphocytes, using a protein called CCR5 located on the surface of these cells. And scientists decided to stop the virus with the help of genetic editing at this stage.

The developed treatment technology looks quite simple. Blood is taken from patients and one of the nucleases mentioned above is added to it. The nuclease finds T-lymphocytes and disables the gene responsible for the production of CCR5 in them, making infection of the cell impossible. After that, the blood cells return to the patients' bloodstream. 

The treatment turned out to be extremely successful: it allowed to reduce the number of copies of the virus in the body of patients so much that they were able to abandon traditional antiretroviral therapy, which is mandatory for all carriers of HIV.

Right now, the same study is being repeated with seven dozen patients.

HIV is not the only deadly virus that can be combated by genetic editing methods. Next in line are hepatitis B virus and human papillomavirus (HPV). Both of them do not have radical (that is, eliminating the cause of the disease) treatment today, while the first leads to cirrhosis and liver cancer, and the second leads to malignant tumors of the cervix. Scientists have already figured out how to "wash" viral DNA from the body with the help of programmable nucleases, but an effective way to deliver genetic "weapons" to infected cells has not yet been developed. 

For the first time, doctors managed to cope with cancer with the help of genetic editing. 

This story began, alas, typically. A one–year-old girl Leila from the UK was found to have leukemia - the most common type of cancer in children. With this type of cancer, patients are most often prescribed chemotherapy, but with aggressive forms of leukemia, it is ineffective. That's exactly what happened with Leila: the prognosis for the baby was disappointing. Then her parents turned to a group of researchers working in a London clinic on the treatment of leukemia by genetic editing methods. The researchers planned to start clinical trials with patients only a year later, however, given the medical history of the child, the researchers decided to take up her treatment. 

To treat Leyla, doctors received T-lymphocytes from a healthy donor. With the help of specially created nucleases, the cells became "invisible" to the antitumor drugs that Leila took. In addition, genes that would have attacked the child's body without genetic editing were deactivated in the donor lymphocytes. Finally, lymphocytes were "given the task" to hunt and kill tumor cells. Only one milliliter of such edited lymphocytes was injected intravenously into Leila, and they worked exactly as the doctors had planned. A few months later, the girl underwent a bone marrow transplant – the final step in the treatment of leukemia. The transplant went well, and now Leila and her parents and sister are already at home, the cancer has gone into remission. "The Attic" told about this story in detail in the issue of "Cheerful News".

This case has become a landmark for many reasons, and one of them is the use of another person's immune cells in the procedure. At first glance, an insignificant nuance means that doctors do not need to make changes to the genome of each individual patient, because pharmacists can create a universal drug for the treatment of leukemia (and other diseases). Several pharmaceutical market giants have already announced the beginning of developments in this area.

Of course, the possibility of "editing" other types of cancer is also being investigated, but so far the prospects look vague. The most promising technology looks to be the "shutdown" of RNA, responsible for the construction of tumor cell proteins. However, so far, unfortunately, this is just a "good idea for the future." 

Alzheimer's disease, cardiovascular diseases, metabolic syndrome (the "harbinger" of type 2 diabetes, which almost every second overweight person has today), respiratory and autoimmune diseases, regenerative medicine – this list of disorders that scientists plan to treat with genetic engineering is not limited to. "Genetic scissors"-nucleases can correct harmful mutations or, conversely, add useful changes to DNA, destroy viral DNA and thus fight many diseases.

And in some cases there are already results, however, so far in animal studies. For example, scientists have managed to remove a cataract-causing mutation from the sperm cells of laboratory mice. The researchers used mice with a Crygc gene mutation – all animals with it inevitably developed cataracts. Specialists "cut out" the mutation and replaced it with a normal sequence of the Crygc gene. Then the "edited" spermatozoa were used to fertilize eggs – as a result, 39 mice were born carrying normal copies of the Crygc gene. 

Using the same technology, according to scientists, it is possible to edit the genome of carriers of the BRCA gene mutation (because of this mutation, Angelina Jolie removed both mammary glands and uterus) that causes breast cancer, as well as carriers of a mutation in the presenilin-1 gene - it is she who supposedly causes the early development of Alzheimer's disease. 

It is worth mentioning: there is no need to expect clinical trials of this method in the near future. This is due to a number of difficulties and unresolved issues. 

At the moment, there are two main delivery methods – ex vivo and in vivo. In the first case, the cells are extracted from the body, "edited" and sent back. In the second case, nucleases are injected directly into the body – either point–by-point or into the systemic circulation (the most promising way to do this is to use viruses as "couriers"). 

The ex vivo method gives researchers more control, but in the body, altered cells can die and, more seriously, such manipulations are not suitable for all cell types.

In vivo, the method is suitable for working with almost any cells and, in addition, allows you to work on several organs at once. Alas, there are also disadvantages here: the immune system can attack unfamiliar cells, and the nucleases themselves can "get the wrong address" and make corrections in the wrong place at all. Increasing the "selectivity" of nucleases is another critically important task to be solved.

At the same time, scientists also face ethical dilemmas: editing the genome of human embryos raises the most questions. Of the 22 countries in Western Europe, such manipulations are prohibited in 15. Opponents talk about both the insecurity of the method and questionable ethics: will the spread of genetic editing lead to the fact that in the future parents will "program" their children? The argument "for" at the same time is one – the opportunity to protect the child from hereditary diseases. And, I must say, so far it looks weak: already now parents can diagnose embryos before implantation during the in vitro fertilization (IVF) procedure. Implanted, of course, the most healthy embryo. 

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Genetic editing for the treatment of diseases is already a reality. Despite the technical and ethical difficulties, sooner or later (and probably still sooner) it will become a common practice. And it gives people hope, which we haven't had until now.

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14.12.2015