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 5

CAV-SCN1A hippocampal injections during the chronic stage reduce DS symptoms.

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CAV-SCN1A hippocampal injections during the chronic stage reduce DS symp...
CAV-GFP or CAV-SCN1A (1 × 109 physical particles) were injected bilaterally into the hippocampi of 5-week-old WT and DS mice. Two weeks after injection, depth electrodes were implanted into the hippocampus at the site of injection. (A) Example traces and (B) quantification of the spike frequencies. (C) Example traces of cortical ECoG recordings. (D) Quantification of the spike frequencies. WT: CAV-GFP (n = 5) ); WT: CAV-SCN1A (n = 3); Epileptic activity was not detected in WT mice: CAV-SCN1A (n = 3); DS: CAV-GFP (n = 6); DS: CAV-SCN1A (n = 5). Statistical analyses: unpaired, 1-sample t test. (E) Mice remaining free of thermally induced (TI) seizures. The dotted lines represent the median seizure temperature. WT: CAV-GFP (n = 15); WT: CAV-SCN1A (n = 8); DS: CAV-GFP (n = 10); DS: CAV-SCN1A (n = 13). Statistical analyses: log-rank test. (F) Left: Spontaneous alternations in the Y maze. The dotted line signifies the chance level, expected from random alternation. The markings above the bars indicate statistical analysis using 1-sample t test relative to 50%. No statistical differences were observed using 2-way ANOVA. WT: CAV-GFP (n = 9); WT: CAV-SCN1A (n = 13); DS: CAV-GFP (n = 11); DS: CAV-SCN1A (n = 10). Right: The distance moved in the open field. WT: CAV-GFP (n = 14); WT: CAV-SCN1A (n = 13); DS: CAV-GFP (n = 13); DS: CAV-SCN1A (n = 13). Statistical analyses: 2-way ANOVA followed by Holm-Šidák post hoc analysis. *P < 0.05; ***P < 0.001.