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 6

CAV-SCN1A hippocampal injection during the severe stage of DS ameliorates the epileptic phenotypes.

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CAV-SCN1A hippocampal injection during the severe stage of DS ameliorate...
(A) Survival curve of WT and DS littermates injected with either CAV-GFP or CAV-SCN1A at P21–P24 (juvenile). WT: CAV-GFP (n = 17); WT: CAV-SCN1A (n = 17); DS: CAV-GFP (n = 52); DS: CAV-SCN1A (n = 45). Statistical analyses: log-rank test. (B) Video monitoring of convulsive seizures 36 hours after injection. DS: CAV-GFP (n = 6); DS: CAV-SCN1A (n = 4). See Supplemental Figure 8 for additional data on individual mice. Statistical analyses: unpaired, 2-tailed t test. (C) Mice remaining free of thermally induced seizures. The dotted lines represent the median seizure temperature. DS: CAV-GFP (n = 20); DS: CAV-SCN1A (n = 32). Statistical analyses: log-rank test. (D–G) Two weeks after injection, depth electrodes (D and E) or cortical electrodes (F and G) were implanted. Example traces (D and F) and quantification of the spike frequencies are presented (E and G). DS: CAV-GFP (n = 5 for E, n = 16 for G); DS: CAV-SCN1A (n = 5 for E, n = 19 for G). No epileptic activity was detected in WT mice injected with either CAV-GFP or CAV-SCN1A (n = 5 for depth electrodes and n = 9 for cortical electrodes). Statistical analyses: Mann-Whitney test (E) or unpaired, 2-tailed t test (G). (H and I) example sIPSC traces (H) and average sIPSC frequency recorded from CA1 pyramidal neurons. Statistical analyses: 2-way ANOVA followed by Holm-Šidák post hoc analysis. (J and K) Representative traces (J), and average excitatory postsynaptic potentials (EPSCs) (K, top) and IPSCs (K, bottom) evoked by CA3 Schaffer collateral stimulation at different stimulation intensities. EPSCs were measured at a holding potential of –60 mV, and sIPSCs were measured at 0 mV. WT: CAV-GFP (n = 11); WT: CAV-SCN1A (n = 8); DS: CAV-GFP (n = 10); DS: CAV-SCN1A (n = 11). Statistical analyses: Mixed model repeated measures ANOVA followed by Holm-Šidák post hoc analysis. *P < 0.05; **P < 0.01; ****P < 0.0001.