Induced pluripotent stem cells for gene therapy of hereditary diseases
The diseased skin has developed into blood
Pyotr Smirnov, "Newspaper.Ru»
The dream of treating congenital diseases with gene therapy has almost come true. Taking skin cells from patients with underdeveloped hematopoiesis, scientists corrected a genetic defect in them, transferred them to a stem state and forced them to differentiate into blood progenitor cells. It remains only to transplant them into the patient's bone marrow.Sometimes I want to imagine the life of scientists and doctors of the last century: armed first with knowledge about the bacterial nature of many of the incurable diseases, and a few decades later with antibiotics, they could rightfully feel like powerful wizards making history.
We are probably no less lucky: from fundamental discoveries in biology to practical implementation in medicine, it may take only a few years, most of which will be spent searching for side effects and complications.
Just a year and a half ago, two research groups reported the creation of induced pluripotent stem cells (IPCs) capable of transforming into any cell of the human body under the influence of control signals. There were no ends to dreams and plans: here you have artificial tissues and organs, and the correction of congenital anomalies, and the replacement of obsolete or defective cells.
In general, all the hopes that were pinned on embryonic stem cells ten years ago, but without the two problems inherent in the latter: firstly, there is no question of immunological compatibility for iPSC - they are obtained from the fibroblasts of the patient's skin, secondly, ethical problems are removed – at least those that are related using embryonic and fetal tissues.
Today, Juan Carlos Ispisua Belmonte and his colleagues have moved one step closer to these rosy dreams: with the help of the mentioned technology, they have obtained cells capable of completely restoring normal hematopoiesis when injected into patients with congenital Fanconi anemia.
Fanconi anemia is a hereditary disease characterized by hypoplasia (underdevelopment) of the bone marrow, pancytopenia – a decrease in the number of all blood cells, as well as abnormalities in the development of the skin (hyperpigmentation), bone system (underdevelopment of the I metacarpal or radius) and / or internal organs (kidneys, spleen). Inherited by autosomal recessive type.
The peculiarity of congenital diseases is that there is a genetic defect in all cells of the body, but it is critical for the functioning of some cells, but not for the work of others. For example, mutations in the dystrophin gene affect muscle cells, but do not cause disorders in the work of blood cells. That is, there is no need to change the genome of all cells of our body during treatment – it is enough to interfere only in the key system; well, it would also be nice to change the genome of germ cells so that "harmful" mutations are not transmitted to children.
In the case of muscles, bones, or the same nervous system, it is not yet possible to imagine such a large-scale genetically engineered effect that would affect all cells. The hematopoiesis system, on the contrary, is an ideal example for demonstrating new technologies of this kind. Its peculiarity is in the central germ, the red bone marrow, where all the cells of "white" and "red" blood are formed.
As predicted by Pappenheim and Maximov, the authors of the stem cell theory itself, it is there that a single precursor is located, renewing the population of blood cells throughout our lives. In 1961, this was clearly confirmed by bone marrow transplantation to irradiated mice, whose blood cells were completely replaced after a while by the descendants of the transplanted predecessors.
In fact, red bone marrow transplantation is still the only method of combating hematopoiesis defects – whether it is severe congenital immunodeficiency, the same Fanconi anemia or the effects of radiation exposure. The problem is only in the selection of a donor, because in the case of transplantation, there is a risk of developing not even the usual "host versus graft" reaction, but a much more severe "graft versus host": after transplantation, the descendants of the transplanted cells assume the role of "defenders". And they evaluate "alienness" by themselves.
Theoretically, you can try to isolate progenitor cells from the patient's own red bone marrow or blood, restore their congenital genetic defect, and then plant them back. But any manipulation with multipotent cells is fraught with the loss of their properties.
It was here that the authors of the publication in Nature remembered about the phenomenon of induced pluripotency, when the ability to transform into any cell of our body is assigned to an ordinary skin fibroblast after transplantation of only four genes - OCT4 (POU5F1), SOX2, KLF4 and c-MYC.
This is what the scientists did: first they restored a genetic defect in fibroblasts obtained from patients, and then turned them into the aforementioned IPCs. This procedure made it possible to avoid two problems at once – the instability of the cell genome in Fanconi anemia and the possible loss of pluripotent properties. The authors note that they managed to make this small "laboratory miracle", which remains the pinnacle of biotechnology, only for three out of six samples isolated from patients with Fanconi anemia.
But from the obtained "pseudo-embryos" in these three cases, it was possible to obtain both erythroid ("red") and myeloid ("white") blood sprouts. And the same success was repeated for another source – keratinocytes, skin epithelial cells.
However, all this is still only in vitro: no one will allow scientists to transplant "repaired cells" to patients from whom they were taken.
Of course, a lot of time will pass before the next clinical trials. But taking into account the fact that bone marrow transplantation is a proven and reliable "cellular technology", and there is not much choice in patients with Fanconi anemia, the introduction of the above method will have to wait less than, for example, gene therapy for diseases of the nervous system. Whenever this happens, we have already witnessed how the history of medicine is being made before our eyes.
Portal "Eternal youth" http://vechnayamolodost.ru/01.06.2009