Frontier Science: Seizure frequency reduced by 80%! Innovative gene therapies show amazing results

Scientists at University College London (UCL) have successfully developed a method that can reduce the excitability of overactive brain cells, which can effectively treat epilepsy - the seizures of the mice in the experiment fell by an average of 80%.

The results of this research have been collated and published in
the well-known academic journal Science.

Many brain disorders, such as epilepsy, are caused by the overactivity of a small number of brain cells, which tend to respond poorly
to drug treatment because therapeutic drugs act on the entire brain and cannot specifically target abnormally excited brain regions/cells.
Therefore, finding how to distinguish between normal brain cells and abnormally active brain cells is crucial for developing targeted therapeutic strategies
.

When it comes to gene therapy, most people's impression stays on the treatment
of genetic diseases.
This therapy alleviates the disease process by introducing functional genes to replace mutated genes, and the popular CRISPR gene editing therapy in recent years is the source of the disease - by correcting the wrong gene sequence to cure the disease
from scratch.
In this latest Science article, scientists apply gene therapy to non-hereditary neurological diseases, opening up a new path
for the application of gene therapy in non-hereditary diseases.

Some neurodevelopmental disorders and neuropsychiatric disorders are characterized by intermittent seizures of pathological activity, in the case of epilepsy, there are many different types of seizures, but they are all caused
by overactive neuronal activity.
Previous studies have shown that despite gene therapies' ability to modulate neuronal excitability, these therapies fail to distinguish between diseased neurons and "healthy" neurons, limiting their application
.
In this study, scientists developed a new type of gene therapy that only initiates expression ("switches-on") in overactive cells and not in normal cells ("switch-off"), thereby successfully distinguishing abnormal brain cells from normal brain cells and further targeting abnormally active cells for targeted treatment
.

Image source: 123RF

To create this gene therapy, the team screened genes known to respond "switches-on" to neuronal stimulation and linked their promoters to potassium channels that reduce the firing activity
of neuronal cells.
The combination of promoter and potassium channels was tested
in mouse models and in vitro miniature brain structures (organoids) differentiated from human stem cells.

After screening, the researchers finally locked on the combination of the promoter of the cfos gene and the KCNA1 potassium channel gene
.
They first expressed the gene combination in cell cultures containing overactive mouse neurons and found that the combination was able to calm the excitability
of neurons.
They then tested them on mouse models of epilepsy, delivering these genes via viral vectors directly to the hippocampus region of epilepsy mice, which is often where epilepsy foci are located
.
Experimental results show that the gene therapy can effectively calm the excitability of neurons during seizures induced by exogenous stimulation, and can also inhibit spontaneous seizures
.
The epileptic mice that received this gene therapy had an average reduction in spontaneous seizures of about 80 percent, some of which were even completely free of seizures, and the therapy did not have any negative effects
on the cognitive abilities of the mice.

Next, the researchers want to demonstrate whether this gene therapy can also achieve significant therapeutic effects
on human neurons.
To do this, the team applied the gene therapy to a culture of human brain organoids derived from human stem cells, and then they simulated epilepsy
by applying convulsants twice to induce hyperexcitability of neuronal cells.
Human neurons successfully expressed potassium channel genes when the first convulsant was added, and neuronal cells stopped epileptiform activity when the second round of convulsants were added, successfully reproducing the results of the study
in a mouse model.

The therapy had a pronounced anti-epileptic effect
in all treated mice.
And unlike other gene therapies that permanently alter the expression of specific genes, the expression of potassium channel genes in this study is designed to be stopped
when abnormal neuronal activity stops.
So, how does it reduce the frequency of seizures? The answer may lie in another key pathological feature of epilepsy: "spikes
.
" Spike refers to: Neurons fire frequently at the same time, and the image they show on the EEG is spike-shaped
.
The scientists found that these brain waves were sufficient to induce the expression of gene therapy, and over time, the treated mice had significantly fewer spikes than the epileptic mice treated with viral vectors (control group).

This may explain why this gene therapy can eventually reduce seizures
.

Image source: 123RF

Since this therapy works by normalizing the excitability of abnormal neuronal cells, rather than targeting a specific disease target or marker, it can theoretically be extended to more neurological diseases, such as Parkinson's disease and schizophrenia
.
The treatment process for these neuropsychiatric diseases is plagued by drug resistance, and this innovative gene therapy, if successfully introduced to the clinic, will undoubtedly bring new treatment options
to these patients.

Dr.
Dimitri Kullmann, a co-corresponding author of the paper, said in an interview with industry media outlet Fierce Biotech: "Although it is too early to tell whether this treatment will translate to clinical use, the results in mice are quite promising
.
Seizures in rodents are often difficult to treat, and other types of gene therapies reported in previous studies have reduced seizure rates in mice to between
about 35 and 50 percent.
Compared to the results achieved so far with other gene therapies, the extent to which seizure remission in this study is quite impressive
.
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