Optimizing the Regional Administration of SCN8a-targeting RNAi Therapy

Wenxi Yu, PhD University of Michigan

Wenxi Yu, PhD – University of Michigan

Co-funded with JAM for Dravet

Mutations in the sodium channel genes SCN1A and SCN8A are a significant cause of Developmental Epileptic Encephalopathies (DEEs), severe seizure disorders. We demonstrated that reduced expression of Scn8a using a specific ASO can prevent the onset of seizures in mouse models of Dravet syndrome and Scn8a encephalopathy. We will build on that success by evaluation of another method for reducing Scn8a expression, the viral administration of an shRNA by injection into targeted brain regions. This method provides two important improvements: longer in vivo persistence that avoids repeated treatments, and protection of spinal motor neurons, that depend on Scn8a. We will use an AAV10 construct with demonstrated effectiveness in reducing Scn8a expression to determine whether regional reduction of Scn8a-N1768D can prevent seizure progression and co-morbidities in these mice.

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