Reacción a "Reactions to study testing gene therapy in mice to treat epilepsy"

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.