Neonatal but not juvenile gene therapy reduces seizures and prolongs lifespan in SCN1B–Dravet syndrome mice
Chunling Chen, Yukun Yuan, Heather A. O’Malley, Robert Duba-Kiss, Yan Chen, Karl Habig, Yosuke Niibori, Samantha L. Hodges, David R. Hampson, Lori L. Isom
Chunling Chen, Yukun Yuan, Heather A. O’Malley, Robert Duba-Kiss, Yan Chen, Karl Habig, Yosuke Niibori, Samantha L. Hodges, David R. Hampson, Lori L. Isom
View: Text | PDF
Research Article Neuroscience

Neonatal but not juvenile gene therapy reduces seizures and prolongs lifespan in SCN1B–Dravet syndrome mice

Abstract

Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) that begins in the first year of life. While most cases of DS are caused by variants in SCN1A, variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are also linked to DS or to the more severe early infantile DEE. Both disorders fall under the OMIM term DEE52. Scn1b-null mice model DEE52, with spontaneous generalized seizures and death in 100% of animals in the third postnatal week. Scn1b-null cortical parvalbumin-positive interneurons and pyramidal neurons are hypoexcitable. The goal of this study was to develop a proof-of-principle gene replacement strategy for DEE52. We tested an adeno-associated viral vector encoding β1 subunit cDNA (AAV-Navβ1) in Scn1b-null mice. We demonstrated that AAV-Navβ1 drives β1 protein expression in excitatory and inhibitory neurons in mouse brains. Bilateral intracerebroventricular administration of AAV-Navβ1 in Scn1b-null mice at postnatal day 2 (P2), but not at P10, reduced spontaneous seizure severity and duration, prolonged lifespan, prevented hyperthermia-induced seizures, and restored cortical neuron excitability. AAV-Navβ1 administration to WT mice resulted in β1 overexpression in brain but no obvious adverse effects. This work lays the foundation for future development of a gene therapeutic strategy for patients with SCN1B-linked DEE.

Authors

Chunling Chen, Yukun Yuan, Heather A. O’Malley, Robert Duba-Kiss, Yan Chen, Karl Habig, Yosuke Niibori, Samantha L. Hodges, David R. Hampson, Lori L. Isom

×

Figure 4

AAV-Navβ1 restores Scn1b-null pyramidal neuron excitability.

Options: View larger image (or click on image) Download as PowerPoint
AAV-Navβ1 restores Scn1b-null pyramidal neuron excitability. (A) Represe...
(A) Representative traces showing evoked repetitive firing of cortical pyramidal neurons of brain slices from untreated WT (black) or null (blue) mice. Repetitive AP firing was evoked by injections of 1,500-millisecond currents from –60 pA to 330 pA (selected responses are shown) at 10-pA steps from RMP. (B) Representative traces showing evoked repetitive firing of cortical pyramidal neurons of brain slices from AAV-Navβ1–treated WT (orange) or null (green) mice. Repetitive AP firing was evoked by injections of 1,500-millisecond currents from –60 pA to 330 pA (selected responses are shown) at 10-pA steps from RMP. (C) I-O curves for AP firing of untreated WT versus null pyramidal neurons in response to current injections. I-O curves were generated by plotting of the number of APs evoked by 1,500-millisecond current injections against current intensities over a range of –60 pA to 330 pA. Values are mean ± SEM of 23 cells from 8 untreated WT mice, 19 cells from 7 AAV-treated WT mice, 15 cells from 4 untreated null mice, or 19 cells from 8 AAV-treated null mice. Asterisks denote significant differences between genotypes (P < 0.0001). (D) I-O curves for AP firing of AAV-Navβ1–treated WT versus null pyramidal neurons in response to current injections. I-O curves were generated by plotting of the number of APs evoked by 1,500-millisecond current injections against current intensities over a range of –60 pA to 330 pA. No significant differences between genotypes.