PhRMA Foundation Pre Doctoral Fellowship in Pharmacology/Toxicology

Project: Research project

Description

De novo mutations in SCN8A have been associated with epileptic encephalopathy. The clinical phenotype includes multiple seizure types that are difficult to treat, and an increased risk of sudden unexpected death in epilepsy. The first reported SCN8A encephalopathy mutation was N1768D, which results in elevated persistent sodium current. This mutation was introduced into the mouse Scn8a gene to make a mouse model. Heterozygous Scn8a-N1768D mice recapitulate phenotypes observed in patients and the increased persistent current. GS967 is a sodium channel blocker with 42-fold preference for persistent current over peak current. Chronic treatment in the heterozygous mice resulted in significant improvement in survival. Electrophysiological recordings of neurons isolated from chronically treated Scn8a-N1768D mice showed reduced persistent and peak current density, despite GS967 not being acutely present. This suggests that GS967 is having additional effects beyond acute sodium channel block that result in a reduction of functional voltage-gated sodium channels on the cell surface. We hypothesize that GS967 alters the expression of voltage-gated sodium channel protein at the cell surface. The major goals of this proposal are to determine the mechanism by which this occurs and to examine this phenomenon across different brain regions, tissue types and voltage-gated sodium channel subtypes.
StatusFinished
Effective start/end date9/1/178/31/19

Funding

  • Pharmaceutical Research and Manufacturers of America Foundation, Inc. (Agreement 12/12/16)

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Toxicology
Voltage-Gated Sodium Channels
Pharmacology
Brain Diseases
Mutation
Sodium Channel Blockers
Phenotype
Sodium Channels
Sudden Death
Epilepsy
Membrane Proteins
Seizures
Sodium
Neurons
Survival
6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine
Brain
Genes
Therapeutics