Have a defective gene and change it for one that does its job well. What seemed like science fiction not long ago is now a reality in clinical practice. We talk about gene therapy, on which CAR-T treatments are based, for example, that have already achieved complete remission of hematological cancer in seven patients in the Community of Madrid. This is achieved by modifying the patient’s lymphocytes by genetic engineering so that they fight the tumor. «Lymphocytes are cells that monitor the appearance of cells with mutations. When there is a tumor cell, the lymphocytes recognize it and eliminate it. When this mechanism fails is when the tumor appears, ”explains Dr. Juan Antonio Bueren, head of the Division of Innovative Therapies at the Center for Energy, Environmental and Technological Research (Ciemat), at the Network Biomedical Research Center (ABC) Ciberer) and at the Jiménez Díaz Foundation Health Research Institute (ISS-FJD).
CAR-T therapy consists of taking the patient’s lymphocytes, genetically modifying them so that they directly recognize a certain type of cell, for example tumor, and reintroducing them into their body. This novel treatment is getting very good results in B lymphocytic leukemias.
resistant to conventional treatments such as chemotherapy.
In general, gene therapy has had its greatest development in the treatment of rare genetic diseases that occur because there is a gene that does not work. “The protein that must be generated from a certain gene is not produced. The best way to treat these patients is to replace the defective gene with one that works normally, ”explains Dr. Bueren. And how is this done? The expert details that the most effective way to get a gene into a cell with the mutated gene is to do it through a genetically modified virus. These viral vectors can be integrative (they insert the gene into the genome of the target cell) or non-integrative (not integrated into the genome). “Right now there are very effective gene therapy protocols with both types of vectors,” says the expert.
In the case of non-integrative vectors, the therapy would lose effectiveness over time if the target cell were a dividing cell, since copies of the therapeutic gene would be diluted. Therefore, it is being applied in tissues with a low rate of cell division, such as liver, neurons and muscles, in diseases such as hemophilia, San Filippo syndrome or spinal muscular atrophy. The viral vector is introduced intravenously or directly into the brain, cerebrospinal fluid or muscle.
Transplant without rejection
For treatments with integrative viral vectors, at present, lentivirus derivatives are used more frequently, which have the great ability to integrate into the genome of cells, even in the bone marrow stem cells that give rise to All blood cells. This means that any pathology that affects the blood cells can be healed by correcting the bone marrow stem cells. In this case, the effectiveness of the process when the vector is inoculated in the patient’s body is low, so it is more effective to extract the cells from the marrow, and in the laboratory (in vitro) put them in contact with the therapeutic vectors. «The target cells are incubated next to the therapeutic vectors, and within a few days they are reintroduced into the patient as if it were a bone marrow transplant from a healthy donor, but with the advantage that there would be no rejection between donor and recipient ”, explains Dr. Bueren.
The expert says that, today, gene therapy is “very safe, effective and very toxic.” The challenge now is not only to add the desired gene (Addition Gene Therapy) to the genetic background of a diseased cell, but to do so at the exact site of the genome in which it is desired (Gene Gene Therapy). “The great leap that has been made so that gene therapy editing is no longer science fiction has been the discovery of proteins such as CRISPR,” he says. This has increased “extraordinarily” the effectiveness of the “recombination” processes that allow “cure” a particular mutation as a means of treating genetic diseases.
“We are living some really interesting years in this field, because this, which was recently science fiction, is now a clinical reality,” says Dr. Bueren. There are already different gene therapy drugs on the market, and “in 2020, the approval of another half dozen is expected, most likely aimed at the treatment of hemophilia, thalassemia, and others,” says the expert. In addition, all clinical trials underway, several of them in Spain, “are very promising.” The expert says that in our country “there are very powerful groups in the field of research into rare diseases, very well coordinated, so we can be proud of what we are doing among all internationally”, he concludes. .