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ResearchIn-Press PreviewCell biologyNeuroscience Open Access | 10.1172/JCI196068

Targeted gene therapy alleviates epilepsy and hyperexcitability in models of SCN2A deficiency

Zaiyang Zhang,1 Jingliang Zhang,1 Xiaoling Chen,1 Brody A. Deming,1 Shivam Kant,1 Purba Mandal,1 Harish Kothandaraman,2 Phillip J. SanMiguel,3 Manasi S. Halurkar,1 Akila D. Abeyaratna,1 Morgan J. Robinson,1 Iuliia Vitko,4 Ronald P. Gaykema,4 Chongli Yuan,5 Nadia A. Lanman,2 Matthew T. Tegtmeyer,5 Dan Wang,6 Guangping Gao,6 Riyi Shi,5 Edward Perez-Reyes,4 and Yang Yang1

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

Find articles by Lanman, N. in: PubMed | Google Scholar |

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

Find articles by Gao, G. in: PubMed | Google Scholar |

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

Find articles by Shi, R. in: PubMed | Google Scholar |

1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, United States of America

2Purdue Institute for Cancer Research, Purdue University, West Lafayette, United States of America

3Purdue Genomics Core, Bindley Bioscience Center, Purdue University, West Lafayette, United States of America

4University of Virginia School of Medicine, Charlottesville, United States of America

5Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, United States of America

6Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, United States of America

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Published November 3, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI196068.
Copyright © 2026, Zhang 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 November 3, 2026 - Version history
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Abstract

Pathogenic SCN2A loss-of-function (LoF) variants can cause severe, refractory epilepsy with limited treatment options. Existing Scn2a-LoF mouse models exhibit few spontaneous seizures, limiting the dynamic range needed to assess therapeutic efficacy. We therefore generated gene-trap Scn2a-deficient mice on the seizure-prone DBA/2J background. These mice experienced hundreds of spontaneous absence seizures per day, characterized by concurrent behavioral arrest and EEG spike–wave discharges (SWDs). Partial restoration of Scn2a expression reduced seizure burden. Electrophysiological analysis revealed impaired action potential waveforms yet increased repetitive firing, alongside coordinated downregulation of voltage-gated potassium channel genes, potentially contributing to hyperexcitability. Given the broad potassium channel downregulation and prior efficacy of KCNA1 gene therapy in refractory seizure models, we selected KV1.1 as a potential therapeutic target and used a drug-controllable adeno-associated virus (AAV) to express human KCNA1. We found that this intervention normalized elevated neuronal firing and reduced spontaneous seizure burden in Scn2a-deficient mice. Extending these findings to a human cell-based platform, AAV-mediated KCNA1 expression also reduced neuronal firing in human cortical organoids carrying a SCN2A-truncating variant identified in patients. Together, these findings provide proof of principle for drug-controllable KCNA1 gene therapy as a promising treatment avenue for epilepsy related to SCN2A LoF variants.

Graphical Abstract
graphical abstract
Supplemental material

View Video 1: Video-EEG showing spike-wave discharges during the light-off period in a Scn2agt/gt mouse.

View Video 2: Video-EEG showing spike-wave discharges during the light-on period in a Scn2agt/gt mouse.

View Video 3: Video-EEG showing a Scn2agt/gt mouse having myoclonus-like activity.

View Video 5: Video-EEG showing a Scn2agt/gt mouse had an unprovoked wild-running episode during the light-off period.

View Video 6: Video-EEG showing a Scn2agt/gt mouse had an unprovoked wild-running episode during the light-on period.

View Video 7: Video-EEG showing a Scn2agt/gt mouse had home cage circling behavior during the light-off period.

View Video 4: Video-EEG showing a Scn2agt/gt mouse had an unprovoked wild-running episode during the light-on period.

View Unedited blot and gel images

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View Supplemental Material List

Version history
  • Version 1 (November 3, 2026): In-Press Preview
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