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ResearchIn-Press PreviewNeuroscienceTherapeutics Open Access | 10.1172/JCI182584

Neonatal but not Juvenile Gene Therapy Reduces Seizures and Prolongs Lifespan in SCN1B-Dravet Syndrome Mice

Chunling Chen,1 Yukun Yuan,1 Heather A. O'Malley,1 Robert Duba-Kiss,2 Yan Chen,1 Karl Habig,1 Yosuke Niibori,3 Samantha L. Hodges,1 David R. Hampson,2 and Lori L. Isom1

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Chen, C. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Yuan, Y. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by O'Malley, H. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Duba-Kiss, R. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Chen, Y. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Habig, K. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Niibori, Y. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Hodges, S. in: JCI | PubMed | Google Scholar |

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Hampson, D. in: JCI | PubMed | Google Scholar

1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States of America

2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

Find articles by Isom, L. in: JCI | PubMed | Google Scholar |

Published January 23, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI182584.
Copyright © 2025, Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 23, 2025 - Version history
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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 brain. Bilateral intracerebroventricular administration of AAV-Navβ1 in Scn1b null mice at postnatal day (P) 2, but not at P10, reduced spontaneous seizure severity and duration, prolonged life span, 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 SCN1B-linked DEE patients. 

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