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Stroke (stroke) has become the first lethal disease in Urban and Rural Areas of China, and the primary cause
Among them, neuronal damage has an almost irreversible effect on the normal life of stroke patients, and in adults, neuronal cells act as permanent cells that cannot regenerate
In recent years, more and more in situ nerve regeneration gene therapies (or neuronal reprogramming) that use neurogenic transcription factors to induce endogenous glial cells to functional neurons in situ are emerging, which may provide a potential treatment window
Mechanism of in situ nerve regeneration therapy
Glial hyperplasia is a common pathological process after brain injury that involves the activation of glial cells to proliferate and become hypertrophied to occupy injured brain regions, and glial cells including astrocytes, NG2 cells, and microglia undergo a reactive response to damage to form a defense system against microbes and cytotoxins invading surrounding tissues
This phenomenon is also widely found
Professor Gong Chen's team from Jinan University and Penn University found that after brain damage in mice, when they were infected with a retrovirus encoding the single transcription factor NeuroD1, reactive glial cells, including astrocytes and NG2 cells, could be reprogrammed into functional neurons
The research team then developed a gene therapy
Characteristics based on AAV nNeuroD1 gene therapy
In terms of efficacy, gene therapy based on AAV nNeuroD1 can regenerate 141 ± 6.
Compared with retroviruses that also take a single NeuroD1 encoding, it was found that when only dividing reactive glial cells were converted into neurons using retroviruses, the number of newly transformed neurons would decrease
Relatively speaking, AAV can infect dividing and non-dividing cells, and the AAV system is able to significantly increase the total number
It is also worth pointing out that because AAV can infect dividing and non-dividing cells, it becomes crucial
Strengths and weaknesses
The team notes that the advantage of this treatment approach is that it can provide a longer treatment window, extending from a few hours to days, weeks or even months
In addition to the significant increase in treatment window, the team's in vivo cell transformation technique also has advantages
The limitation is that it needs to rely on astrocytes, and if the stroke damage is too heavy and even the astrocytes are lost in large quantities, this may require additional treatment, first to reduce cell death, so as to save some glial cells for transformation purposes
Another challenge is that if ischemic injury involves multiple brain regions, such as the cortex, striatum, and hippocampus in the MCAO model, different transcription factors may be needed to produce different subtypes of neurons in different brain regions for effective repair
Summary
In recent years, target-target treatments in neurodegenerative diseases such as Alzheimer's disease, ALS, Parkinson's, etc.
do not seem to see recovery in a hard clinical sense, but stay in the data stage of biomarkers and do not really allow patients to recover
.
And treatments about nerve regeneration may be one way to
be more attractive and potentially therapeutic.
A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion.
Mol Ther.
2020 Jan 8; 28(1):217-234.
doi: 10.
1016/j.
ymthe.
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Epub 2019 Sep 6.
PMID: 31551137; PMCID: PMC6952185.
Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G.
In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model.
Cell Stem Cell.
2014 Feb 6; 14(2):188-202.
doi: 10.
1016/j.
stem.
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12.
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Epub 2013 Dec 19.
PMID: 24360883; PMCID: PMC3967760.