Long‐Term Downregulation of the Sodium Channel Gene Scn8a Is Therapeutic in Mouse Models of SCN8A Epilepsy

Objective De novo mutations of the voltage‐gated sodium channel gene SCN8A cause developmental and epileptic encephalopathy (DEE). Most pathogenic variants result in gain‐of‐function changes in activity of the sodium channel Nav1.6, poorly controlled seizures, and significant comorbidities. In previ...

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Bibliographic Details
Published in:Annals of neurology 2024-04, Vol.95 (4), p.754-759
Main Authors: Hill, Sophie F., Yu, Wenxi, Ziobro, Julie, Chalasani, Sanjna, Reger, Faith, Meisler, Miriam H.
Format: Article
Language:English
Subjects:
Animal models
Animals
Antisense oligonucleotides
Comorbidity
Convulsions & seizures
Disease Models, Animal
Down-regulation
Down-Regulation - genetics
Encephalopathy
Epilepsy
Epilepsy - drug therapy
Epilepsy - therapy
Life span
Mice
Model testing
Mutation
NAV1.6 Voltage-Gated Sodium Channel - genetics
Neonates
Oligonucleotides, Antisense - pharmacology
Oligonucleotides, Antisense - therapeutic use
RNA viruses
RNA, Small Interfering - pharmacology
RNA, Small Interfering - therapeutic use
Seizures
Seizures - genetics
Sodium
Sodium channels
Sodium channels (voltage-gated)
Sodium Channels - genetics
Survival
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Summary:Objective De novo mutations of the voltage‐gated sodium channel gene SCN8A cause developmental and epileptic encephalopathy (DEE). Most pathogenic variants result in gain‐of‐function changes in activity of the sodium channel Nav1.6, poorly controlled seizures, and significant comorbidities. In previous work, an antisense oligonucleotide (ASO) reduced Scn8a transcripts and increased lifespan after neonatal administration to a mouse model. Here, we tested long‐term ASO treatment initiated after seizure onset, as required for clinical application. Methods ASO treatment was initiated after observation of a convulsive seizure and repeated at 4 to 6 week intervals for 1 year. We also tested the long‐term efficacy of an AAV10‐short hairpin RNA (shRNA) virus administered on P1. Results Repeated treatment with the Scn8a ASO initiated after seizure onset provided long‐term survival and reduced seizure frequency during a 12 month observation period. A single treatment with viral shRNA was also protective during 12 months of observation. Interpretation Downregulation of Scn8a expression that is initiated after the onset of seizures is effective for long‐term treatment in a model of SCN8A‐DEE. Repeated ASO administration or a single dose of viral shRNA prevented seizures and extended survival through 12 months of observation. ANN NEUROL 2024;95:754–759
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.26861