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

Erin M. Baker, Christopher Hal Thompson, Nicole Alise Hawkins, Jacy L. Wagnon, Eric R. Wengert, Manoj K. Patel, Alfred L George Jr, Miriam H. Meisler, Jennifer A Kearney*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 for 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 as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8aN1768D/+ 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 Scn8aN1768D/+ mice. Results: GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8aN1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock–induced seizures in Scn8aN1768D/+ and wild-type mice. Chronic treatment of Scn8aN1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8aN1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Significance: Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.

Original languageEnglish (US)
Pages (from-to)1166-1176
Number of pages11
JournalEpilepsia
Volume59
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Sodium Channels
Brain Diseases
Sodium
Seizures
Phenytoin
NAV1.6 Voltage-Gated Sodium Channel
Therapeutics
Channelopathies
Neurons
Mutation
Therapeutic Uses
6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine
Age of Onset
Action Potentials
Pharmaceutical Preparations

Keywords

  • epilepsy
  • epileptic encephalopathy
  • mouse model
  • pharmacology
  • voltage-gated sodium channel

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

@article{126cdd6f418b4ca396ec802666d7fe99,
title = "The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy",
abstract = "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 for 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 as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8aN1768D/+ 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 Scn8aN1768D/+ mice. Results: GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8aN1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock–induced seizures in Scn8aN1768D/+ and wild-type mice. Chronic treatment of Scn8aN1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8aN1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Significance: Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.",
keywords = "epilepsy, epileptic encephalopathy, mouse model, pharmacology, voltage-gated sodium channel",
author = "Baker, {Erin M.} and Thompson, {Christopher Hal} and Hawkins, {Nicole Alise} and Wagnon, {Jacy L.} and Wengert, {Eric R.} and Patel, {Manoj K.} and {George Jr}, {Alfred L} and Meisler, {Miriam H.} and Kearney, {Jennifer A}",
year = "2018",
month = "6",
day = "1",
doi = "10.1111/epi.14196",
language = "English (US)",
volume = "59",
pages = "1166--1176",
journal = "Epilepsia",
issn = "0013-9580",
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}

The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy. / Baker, Erin M.; Thompson, Christopher Hal; Hawkins, Nicole Alise; Wagnon, Jacy L.; Wengert, Eric R.; Patel, Manoj K.; George Jr, Alfred L; Meisler, Miriam H.; Kearney, Jennifer A.

In: Epilepsia, Vol. 59, No. 6, 01.06.2018, p. 1166-1176.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

AU - Baker, Erin M.

AU - Thompson, Christopher Hal

AU - Hawkins, Nicole Alise

AU - Wagnon, Jacy L.

AU - Wengert, Eric R.

AU - Patel, Manoj K.

AU - George Jr, Alfred L

AU - Meisler, Miriam H.

AU - Kearney, Jennifer A

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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 for 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 as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8aN1768D/+ 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 Scn8aN1768D/+ mice. Results: GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8aN1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock–induced seizures in Scn8aN1768D/+ and wild-type mice. Chronic treatment of Scn8aN1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8aN1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Significance: Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.

AB - 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 for 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 as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8aN1768D/+ 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 Scn8aN1768D/+ mice. Results: GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8aN1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock–induced seizures in Scn8aN1768D/+ and wild-type mice. Chronic treatment of Scn8aN1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8aN1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Significance: Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.

KW - epilepsy

KW - epileptic encephalopathy

KW - mouse model

KW - pharmacology

KW - voltage-gated sodium channel

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