New Therapeutic Candidates Identified for SCN8A-Related Epilepsy

 

Caused by a gain-of-function mutation in the SCN8A gene encoding the Nav1.6 sodium channel, SCN8A-related epilepsy is characterized by developmental delay, seizure onset in infancy (first 18 months of life, mean of 4 months), and intractable epilepsy with multiple seizure types. Researchers Talia A. Atkin, Chani M. Maher, Aaron C. Gerlach, and others report the identification of potential new therapeutic candidates in the journal Epilepsia.

The authors of the study first generated cellular models expressing the normal SCN8A sodium channel or one with the gain-of-function mutation responsible for SCN8A-related epilepsy, and then developed an assay for sodium flux in these cells. This assay was used to assess an extensive library of over 1,300 previously approved drugs, including several antiepileptic drugs, to determine which, if any, inhibited sodium influx in cells with mutant SCN8A. Drug candidates so identified were further assessed for concentration-response effects on sodium influx, and electrophysiology measurements were taken to further characterize drug effects.

A total of 90 drugs that inhibited the gain-of-function mutation effects on sodium influx were identified. Of these, 4 were of potential clinical interest, including amitriptyline, carvedilol, nilvadipine, and carbamazepine, which all demonstrated concentration-dependent inhibition of sodium influx in cells with mutant SCN8A.

In contrast to many repurposing studies that focus on just a few drugs, the high-throughput method used in this study allowed the researchers to screen hundreds of on-market drugs. Most of the 90 drugs identified as having an effect on sodium influx have never been tested for this effect previously, thus representing potentially novel mechanistic activities.

"Although (genetic sequencing) can often define the exact mutation that causes a patient's rare disease, the diagnostic findings only occasionally translate into improved therapies. The study's findings demonstrate that a comprehensive high-throughput drug screening approach can identify approved medications that act specifically against the effects of a particular mutation," said Dr. Orrin Devinsky, Director of the NYU Comprehensive Epilepsy Center and one of the senior authors of the study. 

 

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