# Functional Genetics of the Neuronal Sodium Channel Gene SCN8A

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $453,187

## Abstract

ABSTRACT
During the previous funding period, we generated a conditional mouse model of the recurrent sodium channel
mutation SCN8A-p.R1872W that is responsible for the rare, devastating disorder Developmental Epileptic
Encephalopathy (DEE). We demonstrated that expression of the mutant channel in excitatory neurons of the
forebrain reproduces the seizures and sudden death of the human disorder. We also developed an effective
treatment for Scn8a-DEE by intracerebroventricular administration of an antisense oligonucleotide (ASO) that
reduced both mutant and wildtype transcript level throughout the brain, resulting in delayed seizure onset and
extended lifespan. We will build on this important preclinical result by developing improved, longeracting
treatments that will minimize the side effects of excess Scn8a reduction. First, AAV viral delivery of an Scn8a-
shRNA will limit effects to specific brain regions only. Second, the multiple nucleotide substitutions in our
engineered Scn8a-N1768D mutant make it feasible to specifically inactivate the mutant allele by CRISPR/Cas
targeting. The goal of these experiments is to minimize the potential side effects of Scn8a deficiency and to
avoid the repeated treatments required for ASO therapy. Finally, expression of Scn8aR1872W in cerebellar
Purkinje cells results in elevated neuronal excitability. We will characterize mice with specific expression of the
mutant allele in Purkinje cells to gain insight into the role of the cerebellum in the movement and cognitive co-
morbidities that accompany SCN8A-DEE. The work described here will extend basic understanding of SCN8A
pathophysiology and provide pre-clinical evidence regarding future translational potential of regional or mutant-
allele-specific down-regulation of pathogenic variants of SCN8A.

## Key facts

- **NIH application ID:** 10766204
- **Project number:** 5R01NS034509-27
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MIRIAM H MEISLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,187
- **Award type:** 5
- **Project period:** 1996-05-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766204

## Citation

> US National Institutes of Health, RePORTER application 10766204, Functional Genetics of the Neuronal Sodium Channel Gene SCN8A (5R01NS034509-27). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10766204. Licensed CC0.

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