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AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet syndrome.

Overview

Authors: Juan Antinao Diaz1, Ellie M Chilcott1, Amanda Almacellas Barbanoj2, Anna Keegan1, Sonam Gurung3, Valda Pauzuolyte1, Zak Waddington1, Maria Kyriacou1, Amy McTague3,4, J Helen Cross3,4, Stephanie Schorge5, Gabriele Lignani2, Simon N Waddington1, Rajvinder Karda1
ORCID iDs: Juan Antinao Diaz, Ellie M Chilcott, Valda Pauzuolyte, J Helen Cross, Rajvinder Karda
  1. EGA Institute for Women’s Health, University College London, London WC1E 6HX, UK
  2. Research Department of Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
  3. UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
  4. Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK
  5. Division of Biosciences, Medical Science Building, University College London, London WC1E 6BT, UK
Institutions: University College London (United Kingdom); UCL Queen Square Institute of Neurology (United Kingdom); Great Ormond Street Hospital (United Kingdom)
Journal: Molecular therapy. Nucleic acids, volume 37, issue 2, article 102942
Dates: received 14 May 2025; accepted 24 April 2026; published online 30 April 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.omtn.2026.102942 · PMID 42181696 · PMCID PMC13196359 · OpenAlex W4402962112
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2024.09.27.615323
Status: code on request
Categories: human (organism), mouse (organism), epilepsy (population), clinical / translational (subfield)
Methods: Statistics, Evoked potentials, Connectivity
Keywords: MT, delivery strategies, Dravet syndrome, SMEI, gene therapy, AAV, NaV1.1, natural antisense transcript, pre-clinical
Topic: MicroRNA in disease regulation (Cancer Research, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: LifeArc; Great Ormond Street Hospital Children's Charity (VS0122); National Institute on Handicapped Research; Rosetrees; UK Research and Innovation Medical Research Council (MR/S011005/1, MR/T007087/1, MR/V034758/1); Wellcome Trust; National Institute for Health and Care Research; Epilepsy Research Institute UK; NIHR Great Ormond Street Hospital Biomedical Research Centre
Citations: not cited yet (Europe PMC); 63 references in the paper

Abstract

Dravet syndrome (DS) is a severe childhood developmental and epileptic encephalopathy. Symptoms usually manifest in the first year of life and include prolonged severe seizures, developmental delay, severe intellectual disability, and increased mortality. Approximately, 90% of patients carry a heterozygous loss-of-function mutation in SCN1A, encoding a voltage-gated sodium ion channel, NaV1.1. NaV1.1 is expressed in the brain and at a lower level, in the heart. Previous studies have identified a long non-coding RNA (lncRNA), which specifically downregulates SCN1A expression. This natural antisense transcript (NAT) can be modulated by AntagoNATs, small synthetic oligonucleotides. AntagoNATs have shown to improve seizure frequency in DS mice after repeated administration. Here, we have developed new AntagoNATs and incorporated these into an adeno-associated virus serotype 9 (AAV9) gene therapy vector.

We administered two new AAV9-AntagoNAT-H and AntagoNAT-K vectors to newborn Scn1a+/− mice via intracerebroventricular (i.c.v.) and intravenous (i.v.) injection to deliver vector to the brain and heart. AAV9-AntagoNAT-H significantly increased survival, decreased the frequency of febrile and spontaneous seizures. In this proof-of-concept study, we have demonstrated for the first time the delivery of AntagoNAT via an AAV9 vector. Thus, offering the possibility of a one-time treatment for DS patients.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

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Data

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Data and code availability

The data that support the findings of this study are available from the corresponding author, upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 9 keywords, 9 funders, 60 references.

Cite

This paper

Diaz, J. A., Chilcott, E. M., Barbanoj, A. A., Keegan, A., Gurung, S., Pauzuolyte, V., Waddington, Z., Kyriacou, M., McTague, A., Cross, J. H., Schorge, S., Lignani, G., Waddington, S. N., & Karda, R. (2026). AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet syndrome. Molecular therapy. Nucleic acids, 37(2), 102942. https://doi.org/10.1016/j.omtn.2026.102942

BibTeX

@article{diaz2026aav9,
author = {Diaz, Juan Antinao and Chilcott, Ellie M and Barbanoj, Amanda Almacellas and Keegan, Anna and Gurung, Sonam and Pauzuolyte, Valda and Waddington, Zak and Kyriacou, Maria and McTague, Amy and Cross, J Helen and Schorge, Stephanie and Lignani, Gabriele and Waddington, Simon N and Karda, Rajvinder},
title = {{AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet syndrome}},
journal = {Molecular therapy. Nucleic acids},
year = {2026},
month = apr,
volume = {37},
number = {2},
pages = {102942},
publisher = {American Society of Gene \& Cell Therapy},
issn = {2162-2531},
doi = {10.1016/j.omtn.2026.102942},
url = {https://doi.org/10.1016/j.omtn.2026.102942},
pmid = {42181696},
pmcid = {PMC13196359}
}

RIS

TY - JOUR
AU - Diaz, Juan Antinao
AU - Chilcott, Ellie M
AU - Barbanoj, Amanda Almacellas
AU - Keegan, Anna
AU - Gurung, Sonam
AU - Pauzuolyte, Valda
AU - Waddington, Zak
AU - Kyriacou, Maria
AU - McTague, Amy
AU - Cross, J Helen
AU - Schorge, Stephanie
AU - Lignani, Gabriele
AU - Waddington, Simon N
AU - Karda, Rajvinder
TI - AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet syndrome
T2 - Molecular therapy. Nucleic acids
J2 - Mol Ther Nucleic Acids
PY - 2026
DA - 2026/04/30
VL - 37
IS - 2
SP - 102942
SN - 2162-2531
PB - American Society of Gene & Cell Therapy
DO - 10.1016/j.omtn.2026.102942
UR - https://doi.org/10.1016/j.omtn.2026.102942
LA - en
ER -

CSL-JSON

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