Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model
Melody Li, … , Frank Rigo, Steven Petrou
Melody Li, … , Frank Rigo, Steven Petrou
Published December 1, 2021
Citation Information: J Clin Invest. 2021;131(23):e152079. https://doi.org/10.1172/JCI152079.
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Research Article Neuroscience

Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model

Abstract

De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function in SCN2A is seen in some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction in SCN2A expression could substantially improve clinical outcomes. We tested this theory by central administration of a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA in a mouse model of Scn2a early seizure onset DEE (Q/+ mice). Untreated Q/+ mice presented with spontaneous seizures at P1 and did not survive beyond P30. Administration of the ASO to Q/+ mice reduced spontaneous seizures and significantly extended life span. Across a range of behavioral tests, Scn2a ASO-treated Q/+ mice were largely indistinguishable from WT mice, suggesting treatment is well tolerated. A human SCN2A gapmer ASO could likewise impact the lives of patients with SCN2A gain-of-function DEE.

Authors

Melody Li, Nikola Jancovski, Paymaan Jafar-Nejad, Lisseth E. Burbano, Ben Rollo, Kay Richards, Lisa Drew, Alicia Sedo, Jacqueline Heighway, Svenja Pachernegg, Armand Soriano, Linghan Jia, Todd Blackburn, Blaine Roberts, Alex Nemiroff, Kelley Dalby, Snezana Maljevic, Christopher A. Reid, Frank Rigo, Steven Petrou

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Figure 1

Disease phenotype of the Q/+ mouse model.

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Disease phenotype of the Q/+ mouse model. (A) Schematic presentation of ...
(A) Schematic presentation of SCN2A channel depicting 4 domains (D1–D4), each comprised of 6 transmembrane regions, and the intracellular N and C-terminus of the channel. The p.R1882Q variant is predicted to affect the C-terminus of the channel. (B) Images of Q/+ mice undergoing spontaneous seizure at P1 (left) and P25 (right). (C) Survival curves of Q/+ and +/+ mice. (+/+ n = 19, Q/+ n = 22). ****P < 0.0001, log rank test. (D) Body weight measured on P10 and P21 (+/+ n = 7–20, Q/+ n = 7–8). (E) Representative voltage traces from a neuron injected with 100 pA current. Scale bar applies to all traces. (F) Input-output relationship generated for each injected current step (+/+ n = 3 mice, 20 cells, Q/+ n = 3 mice, 14 cells). *P < 0.05 (F (15, 512) = 6.301, 2-way ANOVA with Sidak’s multiple comparison. (G) Input resistance. **P < 0.005 (t = 3.22, df = 31). (H) Rheobase. **** P < 0.0001 (t = 5, df = 31), unpaired t test. Data are represented as mean ± SEM.