Dynorphin-based gene therapy demonstrates long-term suppression of seizures

Written by Sharon Salt, Editor

A new therapeutic concept for the treatment of temporal lobe epilepsy has been developed by researchers from Charité – Universitätsmedizin Berlin (Germany) and the Medical University of Innsbruck (Austria). The treatment, which utilizes a dynorphin-based gene therapy, has been reported to suppress seizures at their site of origin and on demand. The results for this study have been published in EMBO Molecular Medicine.

Temporal lobe epilepsy is the most common form of epilepsy and can lead to memory problems, in addition to impaired learning and emotional control. Current medications that are used to treat individuals with temporal lobe epilepsy are often unable to adequately control the disorder and are associated with severe side effects. At present, the only alternative treatment available includes surgical removal of the temporal lobe.

However, within this recent study, a new treatment method has been developed that involves the selective delivery of a specific gene to nerve cells within the area of the brain from which the epileptic seizures originate. The gene that has been delivered contains information for the cells to synthesize dynorphins, which are naturally produced peptides that can modulate neural activity.

When the gene has successfully been delivered into the nerve cells, it remains there permanently. These cells will then start to produce and store dynorphin. Speaking more about the new technique and its mechanism of action, Christoph Schwarzer (University of Innsbruck), who is a corresponding author of the study, explained: “High-frequency stimulation of the nerve cells, such as that seen at the beginning of a seizure, results in the release of stored dynorphins. Dynorphin dampens signal transduction and, as a result, the epileptic seizure doesn’t spread.”

Schwarzer further explained that as the cells will only release dynorphin when required, this type of gene therapy is termed ‘release on demand’.

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The researchers were able to demonstrate that this gene therapy could suppress epileptic seizures for several months, without any side effects being observed (so far). They anticipate that this is most likely due to the site-specific release of dynorphin and its short duration of action.

In addition to this, the team tested their new treatment by examining tissue samples that were obtained from individuals with epilepsy. The dynorphin-based gene therapy was revealed to significantly reduce the severity and frequency of synchronized nerve cell activity in the tissue samples.

“The results from our study are encouraging, prompting us to hope that this new therapeutic concept could also be successful in humans,” concluded corresponding author, Regine Heilbronn (Charité – Universitätsmedizin Berlin). “We are currently working on the viral vector which ferries the gene to its destination, in order to optimize it for use in humans. Our aim is to have this gene therapy ready for its first ever use in a clinical trial in just a few years.”

Sources: Agostinho AS, Mietzsch M, Zangrandi L et al. Dynorphin-based “release on demand” gene therapy for drug-resistant temporal lobe epilepsy. EMBO Mol. Med. 11, e9963 (2019); www.charite.de/en/service/press_reports/artikel/detail/new_gene_therapy_for_epilepsy_provides_on_demand_release_of_endogenous_substance/