19 February 2009

Stem cells were inherited in tumors

Peter Baranov, "Newspaper.Ru»Israeli scientists have for the first time found donor genes in a brain tumor that arose after a stem cell transplant.

The cell transplant took place in Moscow, but the clinics disown the operation. It cannot be argued that it was the transplant that led to the appearance of the tumor, according to supporters of cell therapy.

Of all human tissues and organs, the nervous system remained inaccessible to scientists and doctors for the longest time. And it's not just the isolation and unique architectonics of intercellular contacts and pathways. For a long time, nerve cells were considered incapable of dividing, and therefore of regeneration – regardless of the "influences" exerted.

It is not surprising that with the advent of such a direction as cell therapy at the end of the last century, the greatest hopes were pinned on the treatment of neurological diseases. Embryonic and fetal cells obtained at different stages of human embryo development (fetal cells – a little later, from 10 to 24 weeks) were considered the most promising and effective biological material.

In such "high-tech and promising" branches of medicine, it is not customary to talk about side effects. But it is the potential risks, coupled with ethical considerations, that until recently remained the main deterrent to the development of this direction.

Stem cells with cancerThe publication of Gideon Reshavi from the Sheba Medical Center at Tel Aviv University is unlikely to influence the opinion of the newly elected US president to lift restrictions on working with stem cells.

It is not a fact that she will convince Roszdravnadzor, which licenses such activities in Russia, to pay more attention to this process.

But the number of wary public will clearly increase, and opponents of stem cells, no doubt, will raise this case to the banners.

Scientists have described a case of tumor development in the spinal cord and brain of a boy with ataxia-telangiectasia after fetal cell transplantation. The transplantation was performed in Moscow.

Ataxia-telangiectasia (Louis-Bar syndrome) is a hereditary disease with cerebellar ataxia, telangiectasia, impaired immunity and a tendency to malignant neoplasms; increased fragility of chromosomes; patients' cells are sensitive to ionizing radiation. Frequency. 1:300,000 newborns.
Cerebellar ataxia appears from the first years of life (after the patient starts walking) and progresses with age. Cerebrospinal ataxia with a violation of deep and vibrational sensitivity appears at the age of 12-15 years, oculomotor apraxia (violation of the functions of the oculomotor nerves) is possible.
These patients have frequent immune disorders, hypoplasia of the thymus, a decrease in the level of immunoglobulins in the serum. Lymphopenia and a decrease in cellular immunity develop early. Telangiectasia – formations of venous origin, appear later than ataxia (at the age of 3-6 years), first on the conjunctiva of the eye (vascular "spiders"), then on the skin of the face, auricles, elbow bends, popliteal pits, in places of skin friction.
There is no effective treatment: symptomatic therapy, vitamin and physiotherapy. Recurrent infections and neoplasms significantly reduce life expectancy. If the patient lives to 35-40 years, muscle atrophy, fascicular twitching are observed.

Now the boy is alive, under the supervision of Israeli specialists and receives only conservative treatment. Neither a repeat operation, nor a course of chemo or radiotherapy was required.

The authors of the article in PloS Medicine (among whom there are no those who directly performed cell transplantation) described a multi–focal glioneuronal tumor - that is, a tumor consisting of both neurons and "supporting and isolating" glial cells.

The very case of the development of this tumor for patients with this syndrome is no exception. Moreover, it is neoplasms of the nervous system isolated from the immune system by semi-permeable barriers that, as a rule, cause the death of these patients, who rarely live to 20 years. But Reshavi and colleagues, who performed an operation in 2006 to remove one of the foci of this tumor in the spinal cord, tried to find a connection between the tumor, first registered on MRI in 2005, and stem cell injections performed in Moscow in 2001, 2002 and 2004.

To some extent, they succeeded: only two types of "donor" cells were found in the tumor. They were convincingly different from the cells of the boy himself – both by the presence of a female sex chromosome and a full copy of the amelogenin gene, defective in patients with Louis-Bar syndrome from birth.

That's just to assume that the tumor was caused by a stem cell transplant, and not the cells migrated to the resulting tumor – it is impossible.

The patient is initially predisposed to the development of a tumor, and it is impossible to reliably determine what became the leading one – cell injection or microenvironment – based only on histological and genetic data of a single tumor focus.

Opinions were divided even in the scientific community: Reshavi himself, who did not want to name the Moscow clinic and communicated with its doctors only through the child's parents, believes that the problem is insufficient "characterization" – roughly speaking, cleaning cells before administration. That is, during injections, cells potentially capable of giving rise to a tumor could get into the nervous system. Anonymous doctors probably have a different opinion on this matter.

Based on a very "stripped-down" protocol of actions from the Moscow clinic provided by parents to Israeli specialists, it is impossible to find out exactly how the "cleaning" was carried out. It does not even indicate at what stage of pregnancy the abortion was performed, and, accordingly, the material for transplantation was taken! But the term in this case plays a key role – the longer it is, the more "differentiated" the cells of the nervous system are and the lower the risk of a tumor, but the smaller the potential positive effect.

Mysterious clinicRecently, three Western companies have received permission for clinical trials of fetal cells in the treatment of neurological diseases – these are ReNeuron in the UK, Geron and StemCells in the USA.

One of the founders of Geron, John Sinden, in an interview with Nature, hastened to assure that "the protocols of the Moscow procedure and our tests have nothing in common," and hedged with the phrase that "one isolated case cannot affect the entire industry."

There are 11 clinics dealing with cell therapy of neurological diseases in Moscow. However, only three of them agreed to comment on the case.

The most original and brief comment "to the Newspaper.En" Dali in the clinic "Davinci": "Stem cells can treat all diseases. I have all the people busy right now to talk to you." Apparently, they are busy treating all diseases.

The Aesthetic Best Center clinic, which has a representative office in Moscow, but is located in the Kazakh Alma-Ata, did not tell us what neurological diseases they treat and what biological material they use. In another place, we were told that they only work with autologous cells, that is, cells obtained from the patient himself.

A detailed comment was obtained from Andrey Stepanovich Bryukhovetsky, MD, General Director of the NeuroVita Clinic for Restorative Interventional Neurology and Therapy and a member of the editorial board of the specialized journal Cell Transplantology and Tissue Engineering. In his opinion, "not everything is so unambiguous and categorical."

"As a rule, children with this disease do not live to be 12-14 years old. The main known cause of death is the occurrence of brain tumors and solid (solid – "Gazeta.Ru" ) tumors due to severe immune system disorders in these patients. There is no treatment for this pathology in the world. Therefore, the death of these patients from a tumor is natural," explained Professor Bryukhovetsky. – The use of fetal and embryonic stem cells during intracerebral and intrathecal administration (such routes of administration were used by "Moscow doctors", according to Reshavi, – "Gazeta.Ru") undoubtedly leads to their migration into the tumor and, accordingly, to the chimerization of the patient. Therefore, the presence of genes and pieces of DNA of another (other) organism after the use of fetal and embryonic material in the brain substance and tumor is absolutely natural and typical."

"Why the authors conclude that this is the reason is not very clear," the professor is surprised.

According to the CEO, his clinic uses autologous material, that is, stem cells only from the patient himself, so the boy was clearly not treated by his subordinates. However, even with the treatment of fetal cells, there are much more positive than negative cases. Reshavi's publication is indeed the first.

"Since 1996, I have been observing a brother and sister from Tbilisi who suffer from the same disease. In 1997, we applied treatment with human fetal cells to these children. The children were hospitalized in our clinic for examination last year. The boy is 24 years old today, the girl is 30 years old. Parents are extremely grateful for the result of improving the quality of life of their children, – said A.S. Bryukhovetsky. – I want to note that we did not use ESCs, which have a huge potential for tumor formation. We used adult neural cells of the human fetus. They have very little potential to form tumor clones. Maybe this explains the positive result and the absence of such complications. Now we use only autologous material, i.e. stem cells obtained only from the patient himself."

The scientist found it difficult to guess where such an operation could take place in Moscow.

To a dead endAccording to the expert, embryonic stem cells and their derivatives, fetal cells, as well as cells obtained from animals, are a dead end:

"You can get a fantastic result, but you will not be able to repeat it, and this is no longer a scientific approach."

Unfortunately, it is impossible to draw direct scientific conclusions that could affect the ongoing research. Firstly, because of the paucity of the protocol, and secondly, because of the inability to establish what was the cause and what was the consequence. Anyway, this relatively well-completed clinical case only confirms the need for careful regulation of such studies.

Portal "Eternal youth" www.vechnayamolodost.ru19.02.2009

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