13 April 2017

Reprogrammed astrocytes against Parkinsonism

Swedish researchers from the Karolinska Institute, working under the guidance of Dr. Ernest Arenas, with the help of genetic engineering restored dopamine-producing neurons of the brain in a rat model of Parkinson's disease, prematurely dying with this disease. As a result, the animals regained the ability to almost normal independent movement.

To date, Parkinson's disease – a common age–related neurodegenerative disease in which the brain loses the ability to produce dopamine - has no effective treatment methods. Dopamine-stimulating drugs do not affect the neurodegeneration process and bring only partial relief, often causing motor disorders known as dyskinesia, as well as unusual side effects such as an obsessive desire to participate in gambling.

Since the 1980s, researchers have been working on an alternative approach to the treatment of Parkinson's disease, consisting in replacing dying dopamine-producing neurons instead of replacing the missing dopamine. In the earliest studies, scientists implanted tissue of fetuses aborted in the first trimester of pregnancy containing dopamine-producing neurons into the brain of patients. Despite the fact that the results of a clinical study conducted in 2011 testified to the partial elimination of movement stiffness and tremor associated with the disease, in about 20% of patients, the procedure caused the development of serious dyskinesia. Even more problematic issues related to the use of embryonic cells are ethical problems and difficulties in obtaining biological material.

Instead, some laboratories have used stem cells to produce dopamine-producing neurons in the laboratory. Transplantation of such neurons into the brain of rats reduced the severity of stiffness, tremor and other manifestations of the disease. Clinical trials of this approach in the USA and Japan are planned to begin this or next year.

The authors went further and proposed an approach that does not require the search for donor cells for transplantation and the use of immunosuppressive drugs to suppress the rejection reaction. It consists in the use of gene–loaded transcription factors of lentiviral vectors for reprogramming astrocytes - numerous auxiliary cells of the nervous tissue of the brain. Such viruses infect various cells, but the genes embedded in them selectively affect astrocytes without harming other cells.

When infected with such therapeutic viruses, some astrocytes are reprogrammed and converted into dopamine-producing neurons, first recorded in the brain of rats 3 weeks after the procedure. 15 weeks after the procedure, the brain already contains a large number of such cells, which indicates the irreversibility of the transformation of astrocytes.

Diagram of the in vivo reprogramming process (from an article in Nature Biotechnology).

Five weeks after therapy, mice that had previously had gait disorders characteristic of Parkinson's disease regained the ability to move normally. This indicates the potential for the use of direct reprogramming of astrocytes as a therapy for Parkinson's disease.

However, there are still many difficulties to overcome before the introduction of the new approach into clinical practice. The therapeutic gene delivery system needs to be improved so that it provides reprogramming of more astrocytes without affecting other cells. Despite the fact that therapeutic viruses entering the brain of mice do not cause visible harm, it may not spread to humans. Currently, the authors are already working on improving the safety and effectiveness of the technique.

Experts also note that the transformed cells will be exposed to the causes that initially caused the development of Parkinson's disease. However, according to observations made in the framework of earlier clinical studies, it takes 15-20 years for the transplanted cells to get sick, which gives the patient a fairly long period of time. It is possible that this period will be increased by partially suppressing the reprogramming of cells after the introduction of a therapeutic virus with the help of a drug and its subsequent activation in case of repeated occurrence of a deficiency of dopamine-producing neurons. The authors claim that the basic technology for developing such strategies already exists.

Article by Pia Rivetti di Val Cervo et al. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model is published in the journal Nature Biotechnology.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Karolinska Institutet: Conversion of brain cells offers hope for Parkinson's patients.


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