IPSC against Parkinsonism
Injection of stem cells into the brain slowed down Parkinson's disease
Polina Loseva, N+1
For the first time, a patient with Parkinson's disease was transplanted neurons derived from his own skin cells. The experiment was kept secret, but it turned out to be absolutely legal and safe. Two and a half years have passed since the operation, during which time no side effects have appeared. During this time, his condition has stabilized – it's too early to talk about progress, but doctors have not found any signs of neurodegeneration.
The study was published in The New England Journal of Medicine (Schweitzer et al., Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease).
Cellular reprogramming technology appeared back in 2006, but there are still not so many clinical applications. The fact is that the process itself – the transformation of adult cells into induced pluripotent cells (an analogue of embryonic stem cells) – is still going on with low efficiency. In addition, embryonic cells are capable of forming tumors, and even after they are differentiated into a specific type of cell, dangerous clones may remain in the culture. Therefore, so far, therapies using reprogramming are rare. For example, in the fall of 2019, the cornea was grown from reprogrammed cells for the first time, and in early 2020 – a "patch" for the heart.
In both cases, Japanese researchers became pioneers – since Japanese biologists came up with the idea of reprogramming adult cells into stem cells, this country has become one of the leaders in the field of cell therapy. In 2018, a project of another method appeared in Japan: scientists gathered to test reprogramming against Parkinson's disease, that is, to turn adult cells into embryonic cells, grow them into precursor cells of neurons and plant them in the patient's brain. Clinical trials started in the fall of 2018, but their results have not yet been published.
The Japanese team was the first to talk about such an experiment, but, as it turned out, not the first to launch it. As STAT magazine found out, a similar plan has been maturing in the USA since 2014. In 2017, when the trial plans were just being made in Japan, the first patient had already received an injection of cells, and now a team of doctors led by Kwang-Soo Kim from McLean Hospital in Massachusetts has published a report on this experimental therapy.
According to STAT, the first patient – an American businessman, former doctor George Lopez – found Kim in 2013 and offered to sponsor his research. By that time, Lopez already knew that he had Parkinson's disease, but he did not expect that doctors would be able to help him. Nevertheless, having received funding and accelerated research, after a few years Kim was already ready to try on Lopez has his own method.
The researchers took human skin cells, reprogrammed them into embryonic stem cells, and then differentiated them into precursors of dopaminergic neurons – the same ones that die in patients with Parkinson's disease. To make sure that their protocol is reliable, Kim and colleagues tested it on humanized mice – these are animals with immunodeficiency that are transplanted with human blood cells. The resulting neurons were implanted into their brains, and then the level of immune aggression was monitored. As expected, if blood cells and neurons were obtained from one patient, there was no immune response, and if from different, inflammation developed in the brain.
At the same time, the authors of the work came up with a way to get rid of undifferentiated cells in culture. To do this, they were treated with quercetin – a plant–derived substance that is used in antitumor therapy - after which no more than one per billion "suspicious" cells remained.
Kim and colleagues kept their experiment secret and did not publish preliminary statements. Nevertheless, it was absolutely legal: they received permission from the FDA to use their method in exceptional circumstances – that is, only in a terminally ill person, and each time the procedure must be agreed upon anew. At the first stage of the work, the FDA approved the introduction of cells only in the left hemisphere of the brain. The department agreed to the second series of injections – in the right hemisphere – only six months later, when it became clear that the procedure did not cause side effects.
Immunogenicity of neurons in the mouse brain. From left to right: immunodeficient mice after neuron transplantation, immunodeficient mice after transplantation of blood cells and neurons from one donor, immunodeficient mice after transplantation of blood cells and neurons from different donors. Blue – cell nuclei, red – lymphocytes, a sign of inflammation. Drawings from the article by Schweitzer et al.
Lopez's condition was monitored by doctors using MRI, including using labeled amino acid-a precursor of dopamine. The more neurons absorb this substance, the more they produce dopamine, therefore, the weaker neurodegeneration. Judging by the MRI, no neoplasms in Lopez's brain have arisen in two years, and neurons began to capture a little more amino acids than before.
Tomograms of George Lopez's brain after surgery. The color indicates the intensity of capture of the labeled amino acid in the injection area. On the right -0 are the results of brain MRI, the arrows indicate the injection area.
The researchers assessed the functional state of the patient on two scales: one was responsible for motor skills, the second for the quality of life. During the experiment, motor skills changed insignificantly, so the authors of the work considered that neurodegeneration in his brain had stopped. The quality of life has improved significantly, however, the researchers note that this assessment is subjective. The patient himself noticed that the number of "thrown hours" when he is unable to work and coordinate his movements decreased from three to one hour a day. He continues to take the same medications as before the operation – this is standard therapy for Parkinson's disease, and the required dosage has decreased insignificantly during the observation period, by only six percent.
About the price of the patient's condition. A – scale of motor skills (red – without taking drugs, blue – during the reception). B – the scale of quality of life (according to the patient).
Kim and colleagues continue to monitor Lopez's condition. They do not exclude that cell therapy may in the long term give an effect that has not yet manifested itself. At the same time, they note that we are not talking about healing from the disease yet, only about stabilizing the condition. In addition, they draw attention to the fact that Lopez did not need immunosuppression – this confirms the safety of using the patient's own reprogrammed cells.
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