Advertisement

ResearchIn-Press PreviewNeuroscienceTherapeutics Open Access | 10.1172/JCI159316

Viral vector-mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome

Saja Fadila,1 Bertrand Beucher,2 Iria González Dopeso-Reyes,3 Anat Mavashov,4 Marina Brusel,5 Karen Anderson,5 Caroline Ismeurt,3 Ethan M. Goldberg,6 Ana Ricobaraza,7 Ruben Hernandez-Alcoceba,7 Eric J. Kremer,3 and Moran Rubinstein8

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Beucher, B. in: JCI | PubMed | Google Scholar |

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Dopeso-Reyes, I. in: JCI | PubMed | Google Scholar |

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Mavashov, A. in: JCI | PubMed | Google Scholar

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Brusel, M. in: JCI | PubMed | Google Scholar

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Goldberg, E. in: JCI | PubMed | Google Scholar |

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Ricobaraza, A. in: JCI | PubMed | Google Scholar

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Hernandez-Alcoceba, R. in: JCI | PubMed | Google Scholar

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Kremer, E. in: JCI | PubMed | Google Scholar |

1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2IGF, CNRS 5203 INSERM U661, Montpellier, France

3Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France

4Sagol School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

7Gene Therapy and Regulation of Gene Expression Program, CIMA University of Navarra, Pamplona, Spain

8Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Find articles by Rubinstein, M. in: JCI | PubMed | Google Scholar |

Published May 16, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI159316.
Copyright © 2023, Fadila 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 May 16, 2023 - Version history
View PDF
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 electrocorticography 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.

Graphical Abstract
graphical abstract
Supplemental material

View

Version history
  • Version 1 (May 16, 2023): In-Press Preview
Advertisement
Advertisement