The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

SUMMARY

Objective

De novo mutations of SCN8A, encoding the voltage-gated sodium channel Nav1.6, have been associated with a severe infant-onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4–5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential toxicity. Functional characterization of several SCN8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases.

Methods

The novel sodium channel modulator GS967 has greater preference for persistent versus peak current and nearly ten-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8a-N1768D/+ mouse model carrying an SCN8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8a-N1768D/+ mice.

Results

GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8a-N1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against MES-induced seizures in Scn8a-N1768D/+ and wild-type mice. Chronic treatment of Scn8a-N1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8a-N1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation.