# SCN8A encephalopathy: disease mechanisms and treatment

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $553,774

## Abstract

PROJECT SUMMARY
The mammalian genome contains four voltage-gated sodium channels that are expressed at high levels in the
central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. This gene family plays an important role in the
etiology of human epilepsy and mutations in each gene are associated with different types of epilepsy. However,
the relationship between altered SCN8A function and epilepsy appears more complex. While we have shown
that mice with loss-of-function Scn8a mutations are more resistant to induced seizures, many de novo gain-of-
function SCN8A mutations have been identified in patients with a range of clinical features including catastrophic
childhood epilepsy, autism, intellectual disability and developmental delay. Individuals with SCN8A mutations
also face an increased risk for sudden unexpected death in epilepsy (SUDEP). The mechanisms by which
SCN8A mutations lead to the observed range of clinically challenging features remain poorly understood, and
current therapies are often woefully inadequate. Our central hypothesis is that the development of the most
effective therapy for SCN8A disorders requires a mechanistic understanding of the precise cell types
and brain regions underlying SCN8A pathologies. Our proposal builds on our recent studies in which we
decoupled the cell types, circuits, and regions underlying seizure generation versus seizure resistance due to
Scn8a haploinsufficiency. We will expand on these findings by studying three different SCN8A variants: R850Q
– one of the most severe and recurrent SCN8A mutations, R1620L – a mutation associated with relatively mild
epilepsy, yet intellectual disability and social dysfunction, and N1768D – a mutation associated with epileptic
encephalopathy. We will study the R850Q mutation in Aim 1 by using a conditional knock-in (CKI) mouse line to
enable cell- and region-selective expression of this variant, which until now was not possible to study due to the
severe phenotype and premature lethality when globally expressed in mice. The CKI R850Q line will be used to
establish the contribution of different cell types to the seizure, behavioral, and biophysical phenotypes associated
with SCN8A dysfunction. In Aim 2, we will implement two parallel approaches to guide the identification of more
efficacious SCN8A therapies using pharmacological and cell-specific manipulations in both the R1620L and
N1768D lines, thereby spanning the range of SCN8A clinical presentations. Given the lack of optimized treatment
strategies for patients with SCN8A mutations, we will conduct the first systematic comparison of selected
antiepileptic and candidate drugs for their ability to decrease spontaneous seizures and SUDEP risk, and
normalize behavior. We will also use a chemogenetic approach to further interrogate cell type-specific
contributions to disease mechanisms and establish the therapeutic potential of selectively modulating the
excitability of excitatory neurons, as well as parvalbumin, somat...

## Key facts

- **NIH application ID:** 10586642
- **Project number:** 1R01NS126392-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Andrew P Escayg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $553,774
- **Award type:** 1
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586642

## Citation

> US National Institutes of Health, RePORTER application 10586642, SCN8A encephalopathy: disease mechanisms and treatment (1R01NS126392-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10586642. Licensed CC0.

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