# Pathogenesis of epilepsy in a SCN8A human mutation mouse model

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $353,281

## Abstract

De novo mutations of SCN8A, the gene that encodes for the sodium (Na) channel isoform Nav1.6, are
known to cause early infantile epileptic encephalopathy 13 (EIEE13). To date, more than 150 SCN8A
mutations have been identified. Patients experience a variety of seizure types and motor features that can lead
to wheelchair dependence. Intellectual disability varies from mild to severe and becomes progressively worst
with seizure onset. Sudden unexpected death in epilepsy (SUDEP) occurs in approximately 10% of patients
and increases significantly if seizures are not controlled. Unfortunately, a majority of patients have drug
refractory epilepsy or a mixed response to anti-epileptic drugs (AEDs).
 Very little is known about the pathogenesis of SCN8A epileptic encephalopathy or treatment options for
patients. In this proposal we will use a highly novel and innovative knock-in mouse model, developed by the
Meisler lab, carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D). The mutation
was identified in a child who presented with refractory epilepsy at the age of 6 months, intellectual disability,
ataxia and SUDEP at 15 years of age. The mouse model exhibits many of the pathological phenotypes seen in
patients, including spontaneous seizures and sudden death. In homozygous mutant mice (D/D), seizures begin
at 3 weeks of age and progress to death within 24 hours. Heterozygous mutant mice (D/+) have later seizure
onset starting at 8 weeks of age and progression to death within one to two months. The availability of this
mouse model provides a unique opportunity to fully investigate the pathogenesis of this devastating human
epileptic encephalopathy and to also test new and selective therapies.
 In this proposal we will investigate when alterations in Na channel physiology and membrane
excitability begin to appear in our model of epileptic encephalopathy, testing both excitatory and inhibitory
neurons within brain regions known to be involved in seizure activity. In Aim 1 we will determine the
pathogenesis of these alterations at specific time points before and after seizure onset using mutant mice. In
Aim 2, we will silence Nav1.6 using virally delivered, dox-inducible, Nav1.6 shRNA, targeting either excitatory
or inhibitory neurons and determine the effects on Na channel activity, neuronal excitability and seizure activity
in mutant mice. We will determine if we can delay the onset of seizures by targeting at a time point before the
onset of seizures and also if we can modulate seizure activity in mice with spontaneous seizures. In Aim 3, we
will test whether our Nav1.6 subtype selective compound (MV1505) can reduce seizure activity in heterozygous
(D/+) mice and delay SUDEP. We will also evaluate two clinically used anticonvulsants (phenytoin and
lacosamide). These studies will significantly impact our current understanding of the physiological
consequences of increased Nav1.6 activity in SCN8A epileptic encephalopathy. They will also p...

## Key facts

- **NIH application ID:** 9836894
- **Project number:** 5R01NS103090-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** MANOJ K PATEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,281
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836894

## Citation

> US National Institutes of Health, RePORTER application 9836894, Pathogenesis of epilepsy in a SCN8A human mutation mouse model (5R01NS103090-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836894. Licensed CC0.

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