Viral vector–mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome
Saja Fadila, … , Eric J. Kremer, Moran Rubinstein
Saja Fadila, … , Eric J. Kremer, Moran Rubinstein
Published May 16, 2023
Citation Information: J Clin Invest. 2023;133(12):e159316. https://doi.org/10.1172/JCI159316.
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Research Article Neuroscience

Viral vector–mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome

Abstract

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector–mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally induced seizures, corrected background electrocorticographic activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof of concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

Authors

Saja Fadila, Bertrand Beucher, Iria González Dopeso-Reyes, Anat Mavashov, Marina Brusel, Karen Anderson, Caroline Ismeurt, Ethan M. Goldberg, Ana Ricobaraza, Ruben Hernandez-Alcoceba, Eric J. Kremer, Moran Rubinstein

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Figure 1

Transcriptional control of transgene expression in CAV-2 vectors following injection into the mouse hippocampus.

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Transcriptional control of transgene expression in CAV-2 vectors followi...
CAV-2 vectors containing various promoters upstream of an mCitrine ORF were generated. Physical particles (1 × 109) of each vector were injected bilaterally into the hippocampus of adult mice (n = 5 mice/vector). mCitrine expression is shown by immunohistological DAB staining (dark brown). All the sections were counterstained with cresyl violet. The left-hand column shows a representative hemisphere, the second column shows the hippocampus (magnification of black box in the first column), the third column shows transgene expression in the neocortex (magnification of white box in the first column), and the fourth column shows transgene expression in the CA1 region (magnification of yellow box in the second column). (A–D) CAG promoter–driven mCitrine expression. (E–H) hSyn-driven mCitrine expression. (I–L) NSE-driven mCitrine expression. (M–P) Dlx-driven (Dlx5/6-driven) mCitrine expression. PL, pyramidal cell layer; SO, stratum oriens; SR, stratum radiatum; V, ventricle; CA1, hippocampal CA1 region. Scale bars: 1 mm (A, E, I, and M) 250 μm (B, F, J, and N), 10 μm (C, G, K, and O), and 50 μm (D, H, L, and P).