Viral vector–mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome
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
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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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 9

Concomitant thalamic and hippocampal injection of CAV-SCN1A in juvenile mice improves DS comorbidities.

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Concomitant thalamic and hippocampal injection of CAV-SCN1A in juvenile ...
(A) Survival of DS mice injected with either CAV-GFP or CAV-SCN1A. DS: CAV-GFP (n = 48); DS: CAV-SCN1A (n = 31). Statistical analyses: log-rank test. (B) ECoG electrodes were implanted in a subset of mice, and their seizures were monitored for 5 days after injection DS: CAV-GFP (n = 4; 2 died, the right y axis depicts survival); DS: CAV-SCN1A (n = 4). Statistical analyses: repeated measures ANOVA. (C–E) Cortical electrodes were implanted 2 weeks after injection. Example traces (C) and quantification of the spike frequencies are depicted (D). Statistical analyses: unpaired, 2-tailed t test. (E) Total ECoG power (0.5–100 Hz) WT: CAV-GFP (n = 10); WT: CAV-SCN1A (n = 6); DS: CAV-GFP (n = 6); DS: CAV-SCN1A (n = 10). Statistical analyses: 2-way ANOVA followed by Holm-Šidák post hoc analysis. (F) Mice remaining free of thermally induced seizures. The dotted lines represent the median seizure temperature. DS: CAV-GFP (n = 18); DS: CAV-SCN1A (n = 15). Statistical analyses: log-rank test. (G–I) CAV-SCN1A corrects the performance of DS mice in the novel location test. (G) The experimental paradigm: Mice were allowed to explore the area and 2 objects for 15 minutes. Twenty-four hours later (H), one of the objects was changed (novel object) and mice were allowed to reexplore the area. (I) The third phase: 1 hour later, the novel object was moved to a new location. WT: CAV-GFP (n = 18); WT: CAV-SCN1A (n = 12); DS: CAV-GFP (n = 8); DS: CAV-SCN1A (n = 13). Statistical analyses: 2-way ANOVA followed by Holm-Šidák post hoc analysis. *P < 0.05; **P < 0.01; ***P < 0.001.