Gene-based cell therapy
Ischemic stroke is a condition that occurs against the background of brain tissue damage due to impaired blood circulation in the vessels and is accompanied by various neurological signs. The damage provokes active division of glial cells. American scientists have figured out how to convert glial cells into neurons.
There are about 86 billion neurons in the brain, but billions of them can be lost after a stroke, even of moderate severity. To restore motor functions, it is necessary to regenerate brain cells.
The old approaches were based on neural stem cells (NSCs) and transplanted neural progenitor cells. Although the latter approach has shown promising results, it has not passed clinical trials. The use of NSCs led only to reactive astroglial division, and not to the appearance of neurons. In addition, foreign NSCs often come into conflict with the immune system. However, the biggest obstacle to brain recovery is that neurons are almost incapable of self-regeneration. Over the past few decades, many clinical studies have failed, mainly because none of them has been able to restore enough new neurons to make up for the lost ones.
In this study, scientists used glial cells – the most common type of cells in the brain. They have supportive and immune functions, are located around neurons throughout the brain, remaining capable of cell division and regeneration, and in fact actively do it to heal the brain. This is how glial scars are formed in the brain after injury.
Scientists have been working on glial cells located in the brain next to already dead cells, turning them into neurons. The rationale behind this method is that the glial neighbors of neurons probably originate from the same cell type, which facilitates the transformation.
Earlier studies by the same group of scientists showed how the gene encoding the neural transcription factor NeuroD1 transforms neuroglia cells into neurons with functional neural activity in the brains of mice with Alzheimer's disease. This was aptly called "cell therapy based on gene therapy." However, only a small number of cells were successfully transformed due to an incorrectly selected retroviral vector used to deliver the therapeutic gene to the brain.
This time, the AAV viral vector was chosen, which was successfully used in many similar experiments and infected both dividing and non-dividing cells. The gene was loaded into AAV and thus delivered to the motor cortex of mice on the 10th day after the stroke, when reactive astrogliosis was shown to occur.
This system was created to ensure the expression of higher or significant levels of NeuroD1 in damaged areas, especially inside scar glial cells, turning them into nerve cells in such a way that the number of functioning neurons in the damaged area increased dramatically and reduced the loss of brain tissue. The scientists noted that a third of the dead neurons were replaced by transformed astroglia, while the other third was protected from injury. This contributed to the restoration of the nervous system. The transformations were confirmed by RNA sequencing methods and immuno-staining procedures. Motor tests, such as extracting food pellets and walking on a grid, were performed both before and after ischemic injury and showed recovery of brain function to 80% or more of the level established before the injury
The new neurons were surprisingly similar to the old ones, that is, it can be assumed that the type of cell that gives rise to astroglia also affects the type of neurons.
Moreover, the newly formed nerve cells functioned as they should, generating nerve impulses and forming connections with other "original" neurons in synaptic networks. These neurons grew long axons in the right direction to reach and establish contact with the corresponding target cells, and in general this process helped to accelerate the recovery of motor functions in mice.
Another advantage of the new approach is that even 10 days after an ischemic injury, an effective astroglia transformation can occur. This greatly expands the possibilities for treating patients in remote locations or in underdeveloped regions. The brain is rich in glial cells, which makes it possible to use them everywhere as a resource for the regeneration of neurons.
Scientists plan to further test this technology and, ultimately, create a clinically effective treatment method for the benefit of millions of patients around the world.
Chen et. al's article A NeuroD1 AAV-Based Gene Therapy For Functional Brain Repair After Ischemic Injury Through In Vivo Astrocyte-To-Neuron Conversion is published in the journal Molecular Therapy.
Elena Panasyuk, portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the PennState Eberly College of Science: Gene therapy helps functional recovery after stroke.