First pharmacological treatment option for patients with severe form of epilepsy

Epilepsy comes in many forms. People affected by a genetically determined variety have severe epileptic seizures from the first year of life. The disease is accompanied by serious developmental difficulties: it is difficult for them to walk, they have difficulty concentrating and later have problems with speech, spelling and arithmetic.

Until now, this form of epilepsy has been difficult to treat with the usual medications. Researchers in Tübingen have used a drug that is actually approved for the treatment of multiple sclerosis for the first time. It directly counteracts the underlying genetic defect and successfully alleviates symptoms in patients, reports the team led by Dr Ulrike Hedrich-Klimosch, Dr Stephan Lauxmann and Professor Dr Holger Lerche of the Hertie Institute for Clinical Brain Research, l ‘University Hospital and the University of Tübingen. This implies that for the first time, children and adults with the disease will have access to pharmacological treatment. The results were published in the journal Science Translational Medicine.

The cause of this form of early childhood epilepsy is a rare genetic defect. mutations in the KCNA2 gene lead to defective potassium channels in the brain.

Potassium channels are small pores located in the cell membrane of nerve cells and are important for the transmission of electrical signals. In some subtypes of the disease, mutations lead to increased activity of the channel. In these cases, we speak of a gain-of-function mutation. “

Dr. Ulrike Hedrich-Klimosch, first author and biologist

For the first time, the research team used a therapeutic drug that specifically targets this point. “In this case, therapy linked to the cause must inhibit the increase in channel activity,” explains co-lead author and neurologist Lauxmann. “One of these channel blockers is the active substance 4-aminopyridine. It specifically inhibits potassium channel hyperactivity and is the active compound in a drug approved for the treatment of gait disturbances in patients with multiple sclerosis. In cooperation with eight other centers around the world, the team treated eleven patients in n-of-1 trials with the drug. The results were encouraging: symptoms improved in nine of them. “The number of daily epileptic seizures decreased or disappeared altogether. Patients were generally much more alert and mentally better in everyday life. Their speech also improved after starting the drug treatment. “

The drug does not work for all subtypes of the disease. In some cases, the mutation of the gene leads to a restricted activity of the potassium channels. The researchers created a database so that doctors could quickly decide if the drug can help a patient with a newly diagnosed diagnosis. KCNA2 genetic defect or not. It lists the different mutations of the KCNA gene family and the associated effects on the potassium channel. In this way, therapy can be started quickly and the often severe course of the disease can be relieved.

“Epilepsies caused by mutations in the KCNA2 gene are very rare diseases. In the world, no more than 50 cases are known,” reports the head of the study and neurologist Lerche. Developing a drug suitable for these “medicine orphans” is generally too expensive and not profitable enough for pharmaceutical companies. “We are all the more pleased that we can help these patients individually with what is called drug reorientation: the use of drugs that are in fact approved for other diseases.”

The research team received the Eva Luise Köhler Research Prize for Rare Diseases 2018 for carrying out the project. The study was also supported by the FOR-2715 research group. The study was also funded by the FOR-2715 research group of the German Research Foundation (DFG) on the topic “Epileptogenesis of Genetic Epilepsies” and the Research Network for Rare Ion Channel Disorders (“Treat- ION ”) from the federal government. Ministry of Education and Research (BMBF).