Drug-Resistant Epilepsy, New Hope from the Light of Fireflies: The Study

There light of fireflies will no longer light up only the summer nights, but It could also brighten the future of people with drug-resistant epilepsyforms refractory to the drugs available today, which affect one in three patients. Hope comes from a Italian study published in ‘Nature Communications’, conducted by a team from the Italian Institute of Technology (IIT) coordinated by Fabio Benfenati, in collaboration with the IRCCS San Martino Hospital and the University of Genoa. The work, funded by IIT, San Martino, the University of Genoa and the Prin program (Projects of Relevant National Interest) of the Ministry of University and Research, describes “an innovative approach for the treatment of epilepsy, which exploits the bioluminescence of fireflies to prevent the neuronal hyperactivity typical of epileptic seizures”. The first preclinical data are promising.

With 550 thousand cases in Italy and over 50 million globally – they recall from IIT – Epilepsy is one of the most widespread neurological diseases, so much so that since 2020 it has been recognized by the World Health Organization as a social disease. It is characterized by excessive activation of certain neurons, which alters the normal functioning of the brain. Although most patients benefit from available therapies, approximately one third still do not respond to treatment. An alternative is offered by optogenetics, a technique that genetically modifies neurons so that they express opsins, proteins capable of influencing the activity of nerve cells when exposed to light. Optogenetics allows us to block the pathological activation of pathological neural tissue, bringing the activity of neurons back to physiological levels and defusing epileptic seizures in the first place. However, this strategy requires the insertion of optical fibers into the brain to generate the light necessary for the opsins to function. To bypass this invasive step, The Center for Synaptic Neuroscience and Technology of the IIT has developed a system capable of activating itself autonomously and in a targeted manner directly inside epileptic neurons, returning them to their natural state.

A Hope in Luciferase

“Our approach is based on 3 elements that are produced directly in all nerve cells thanks to genetic modification – explains Caterina Michetti, first author of the study, researcher at the University of Genoa and IIT – It is an opsin connected to a sensor and a bioluminescent molecule, a luciferase, the same protein that allows fireflies to emit light. The administration of the substrate, essentially a drug that luciferase consumes to produce the light signal, allows us to promote the activation of the opsin without needing to insert optical fibers”.

The idea of ​​luciferase is not the only novelty of the ‘made in Genoa’ strategy: “The sensor solves the problem of timing and localization, determining when and in which neurons to activate the circuit to prevent incoming epileptic seizures”, the researchers underline. “Our system – explains Elisabetta Colombo, co-coordinator of the study and researcher at the Center for Synaptic Neuroscience and Technology of the IIT – is equipped with a sensor that perceives the acidification of the neuron, an exclusive characteristic of epileptic neurons, thus creating a closed circuit. Thanks to the administration of the drug that activates luciferase, our sensor checks whether the neuron is healthy or epileptic, and only in the latter case is the opsin activated, which brings neuronal activity back to physiological levels”.

The testing of a therapy based on this approach is still at the preclinical stage, but the results show “a decrease greater than 3 times in the number of epileptic seizures and a reduction of 32%”, practically a third, “in the duration of the attacks compared to the untreated group”, reports the IIT.

“The model developed – comments Benfenati, director of the Center for Synaptic Neuroscience and Technology at IIT – represents a potentially promising approach for the treatment of chronic epilepsy refractory to drugs, regardless of the specific cause, genetic or non-genetic, especially for cases in which surgery is not possible. The next step consists in optimizing the drug administration method, so that the system can remain active in the brain for a long time and intervene promptly when necessary”.