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Reactions to study testing gene therapy in mice to treat epilepsy

Research has tested a gene therapy method that targets overactive cells to treat epilepsy in mice. The results are published in the journal Science.

03/11/2022 - 19:00 CET
Expert reactions

Serratosa - Epilepsia (EN)

José María Serratosa

Neurologist specializing in epilepsy at the Hospital Universitario Fundación Jiménez Díaz.

Science Media Centre Spain

This is a work of excellent quality carried out by a research group of recognized prestige in the field of epilepsy. The work has been led by researchers from the Department of Clinical and Experimental Epilepsy at the University College of London, one of the most advanced departments in clinical and epilepsy research in the world. The work involves experiments with an adeno-associated virus containing a promoter and a gene that, once activated by neuronal activity corresponding to an epileptic seizure, inhibit neuronal activity. In other words, the system works on demand of the epileptic activity. Thus, we would have a treatment that would inhibit neuronal epileptic activity only in the event of a spontaneous epileptic seizure. The experiments were performed on mouse models of epilepsy and on neuronal cells in culture.  

The work provides a very novel treatment approach for patients suffering from drug-resistant epilepsy, who represent 30% of the total number of patients with epilepsy, probably about 100,000 in Spain. This treatment route would be an alternative to the usual treatment for these patients, which consists of treatment with anti-crisis drugs or resective surgery. This involves the ablation of part of the brain tissue which, in addition to being aggressive, can affect different motor or cognitive functions. It also has the advantage that the physiological alteration introduced is only induced in the event of a crisis and not during normal brain activity.  

Although work remains to be done for its preclinical and clinical development, it is likely that this form of treatment will be established in the near future. In addition to the technical challenges in humans (e.g. brain area and injection system), it needs to be demonstrated that this form of treatment does not produce relevant adverse effects and to investigate how it could selectively target different neuronal groups.


The author has declared they have no conflicts of interest

Ángel Aledo - terapia epilepsia EN

Ángel Aledo Serrano

Neurologist specialising in epilepsy at the Ruber Internacional Hospital

Science Media Centre Spain

Epilepsy affects about 1 % of the population worldwide and for almost one third of people with epilepsy, medication is not enough to control seizures and have a good quality of life. Over the past 30 years, more than 20 different treatments for epilepsy have been developed. However, these have failed to reduce the proportion of refractory epilepsies (those that do not respond to drug treatments). This makes the need for new avenues of treatment all the more necessary.  

In recent years, gene therapies or other genetically targeted therapies are being developed for many types of epilepsies caused by specific mutations (pathogenic variants), such as Dravet syndrome (related to the SCN1A gene). However, these treatments will only work for specific causes, and we will need a different therapy design for each epilepsy (most of them rare or infrequent diseases). This work is encouraging, especially because if confirmed to be effective in patients, it would be useful for the most common group of epilepsies, the so-called focal epilepsies (related to a focus or lesion in the brain), in both children and adults.  

Colleagues at the University College of London have made it possible with this treatment, using a viral vector (adeno-associated), to silence a gene that is only activated by seizures, so it could treat seizures without "switching off" the healthy activity of the patient's neurons. They have shown that this can be useful in animal models. The next step will be to conduct clinical trials in patients with refractory epilepsy. Caution must always be exercised with these preclinical (laboratory) studies and clinical development is still years away, but the data they show and the novel approach give hope to the whole epilepsy community. 

The author has declared they have no conflicts of interest

Rubén Hernández - terapia epilepsia EN

Rubén Hernández Alcoceba

Researcher of the Gene Therapy and Regulation of Gene Expression Programme at Cima (Centre for Applied Medical Research) University of Navarra

Science Media Centre Spain

The team led by Dr Gabrielle Lignani at University College London presents a new therapeutic mechanism of action for epilepsy, which could also be applied to other neurological disorders involving hyperactivity of neuronal circuits (Parkinson's disease, schizophrenia, obsessive-compulsive disorders, etc.).  

It is known that the transfer of genes that inhibit neuronal activation (such as the voltage-dependent potassium channel Kcna1) can have an anti-epileptic effect. The main novelty of this study lies in the system used to control the expression of this gene. In other words, in which cells, at what time and with what intensity the protein (the channel) encoding this gene is produced. The researchers have used a regulatory sequence (promoter) derived from the cFos gene, which increases its expression when the neurons are in a high state of activation. This makes it possible to establish a homeostatic mechanism similar to that which regulates many biological processes. Neurons expressing Kcna1 under the control of the cFos promoter experience an inhibitory effect only when their activity is excessive, but can maintain their normal functions.  

This prestigious team of researchers has used a gene therapy vector derived from adeno-associated viruses (AAV) to transfer the cFos-Kcna1 system to neurons in culture and mouse models of epilepsy. The results indicate a clear reduction in epileptic activity without alterations in the behavioural tests studied in the animals. AAV vectors have shown a degree of safety, efficacy and stability compatible with their clinical use in other diseases, making these results relevant not only scientifically but also medically.  

However, there are still major hurdles to overcome for this strategy to become a new treatment. Any gene expression control system has an optimal dose range that is difficult to establish in humans, due to the heterogeneity of patients. On the other hand, immune responses to the vector make the possibility of multiple dosing extremely difficult. Finally, success in epilepsies of non-focal origin would require improvements in the ability of the vectors to diffuse through different brain structures. It is to be hoped that the dynamic field of gene therapy will provide solutions to these difficulties as the scope of application of this neuronal activity control system is investigated in more detail. 

He declares that he has no conflict of interest, beyond the fact that he is developing a therapeutic strategy for a genetic disease that causes epilepsy (among other manifestations).

On-demand cell-autonomous gene therapy for brain circuit disorders
  • Research article
  • Peer reviewed
  • Animals

Qiu et al.

Study types:
  • Research article
  • Peer reviewed
  • Animals
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