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The Future of SCN1A Gene-targeting Research for the Treatment of Dravet Syndrome

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Published Online: Jun 8th 2023 touchREVIEWS in Neurology. 2023;19(2):Online ahead of journal publication DOI: https://doi.org/10.17925/USN.2023.19.2.1
Authors: Rajvinder Karda
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Abstract:
Overview

Rajvinder Karda
Dr Rajvinder Karda is a lecturer In gene therapy at the Institute for Women’s Health, University College London. She completed her PhD in gene transfer and neuroscience at Imperial College London in 2016. Her research team mainly focuses on developing preclinical gene therapy and RNA editing treatments for childhood epilepsy. She also collaborates on preclinical gene therapy projects for rare childhood metabolic disorders. She is currently a board member of the British Gene and Cell Therapy Society and chairs the Public and Patient Engagement series. She is also a member of the Scientific Advisory Committee for the Dravet Syndrome Foundation Charity in Spain.

Keywords

Dravet syndrome, epilepsy syndromes, gene therapy, NAV1.1 voltage- gated sodium channel, paediatric neurology, rare diseases, SCN1A gene

Article:

Dravet syndrome is a rare genetic disorder that affects approximately 1 in 15,700 individuals. It is one of the most severe epilepsy syndromes of early childhood, with high morbidity and mortality rates.1,2 It is characterized by seizures that begin in infancy and can lead to intellectual disability, developmental delays and a range of other neurological problems.3 The SCN1A gene has been identified as the primary genetic cause of Dravet syndrome, with 80% caused by mutations in the SCN1A gene. Research has focused on developing treatments to target this gene.4 In this expert interview, Rajvinder Karda addresses the current status of SCN1A gene-targeting research for the treatment of Dravet syndrome, discusses the potential for future developments in this field and some of the challenges that researchers face in developing effective treatments. She also highlights her current research project to develop a gene therapy for Dravet syndrome, co-funded by Dravet syndrome UK in partnership with Great Ormond Street Hospital Children’s Charity, UK.

Q. Could you give us a brief overview of the SCN1A gene-targeting research project you are running at Great Ormond Street Hospital?

Approximately 80% of people with Dravet syndrome have a loss of function mutation in the SCN1A gene, which encodes a voltage-gated sodium ion channel, Nav1.1.5 This channel is present in brain cells and allows typical firing patterns between these cells. Affected brain cells containing the mutated Nav1.1 channel result in abnormal firing.

Our research project aims to develop a gene therapy treatment for Dravet syndrome. Our approach involves delivering a novel sequence in an adeno-associated virus to increase the healthy SCN1A gene expression and, therefore, restore the Nav1.1 function. The aim is to deliver this treatment to a clinically relevant mouse model for Dravet syndrome, to ameliorate the disease symptoms.

Q. What are some of the key challenges associated with the use of gene-targeting therapies in treating Dravet syndrome?

The key challenges associated with gene-targeting therapies is off-target effects. In our gene therapy treatments, we have overcome this challenge by designing the viral therapy to target the specific cells that express the SCN1A gene.

Q. If successful, how might this gene-targeting therapy impact clinical practice and the lives of people living with Dravet syndrome, and their families?

If our treatment is successful in our preclinical study, this will provide a one-off long-term treatment option for people living with Dravet syndrome and hopefully reduce or completely remove the disease symptoms. Though still at an early stage in the project, the next step following a successful preclinical study would be for clinical studies to be conducted. In addition to the SCN1A gene-targeting research project at Great Ormond Street Hospital, other organizations have treatments for Dravet syndrome that have either started a clinical trial or are due to start one in 2026.6,7

Q. What do you consider the future directions in the development of treatments for Dravet syndrome?

As the field of gene therapy is continuing to develop, this has provided many different forms of long-term effective genetic therapies for Dravet syndrome. This provides the possibility of significantly ameliorating the disease symptoms long term.8–14

Article Information:
Disclosure

Rajvinder Karda no financial or non-financial relationships or activities to declare in relation to this article.

Compliance With Ethics

This article is an opinion piece and does not report on new clinical data, or any studies with human or animal subjects performed by the authors.

Review Process

This is an expert interview and as such has not undergone the journal’s standard peer review process.

Authorship

The named author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval for the version to be published.

Correspondence

Rajvinder Karda, Institute for Women’s Health, 84- 86 Chenies Mews, London WC1E 6HU, UK. E: r.karda@ucl.ac.uk

Support

No funding was received in the publication of this article.

Access

This article is freely accessible at touchNEUROLOGY.com © Touch Medical Media 2023

Acknowledgements

Dravet Syndrome UK provided support to produce the expert interview article. The SCN1A gene-targeting research project is co-funded by Dravet Syndrome UK in partnership with Great Ormond Street Hospital Children’s Charity. Medical writing support was provided by Touch Medical Media and funded by Touch Medical Media.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this study.

Received

2023-03-20

References

1. Dravet Syndrome FoundationWhat is Dravet syndrome2023Available athttps://dravetfoundation.org/what-is-dravet-syndrome/#:~:text=Dravet%20syndrome%20is%20a%20clinical,a%20mutation%20exclude%20the%20diagnosis (Date last accessed: 29 March 2023)

2. Connolly MBDravet syndrome: Diagnosis and long-term courseCan J Neurol Sci2016;43(Suppl. 3):S38. DOI: 10.1017/cjn.2016.243.

3. National Organization for Rare DisordersDravet syndrome – symptoms, causes, treatment2023Available at: https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum/ (Date last accessed29 March 2023)

4. Ding JLi XTian Het alSCN1A mutation-beyond dravet syndrome: A systematic review and narrative synthesisFront Neurol. 2021;12:743726DOI10.3389/fneur.2021.743726.

6. ClinicalTrials.govA clinical study to evaluate the safety and efficacy of ETX101 in infants and children with SCN1A-positive Dravet syndrome (endeavor). ClinicalTrials.gov identifier: NCT05419492Available at: https://clinicaltrials.gov/ct2/show/NCT05419492 (Date last accessed4 May 2023)

7. ClinicalTrials.govAn open-label extension study of STK-001 for patients with Dravet syndrome. ClinicalTrials.gov identifier: NCT04740476Available athttps://clinicaltrials.gov/ct2/show/NCT04740476 (Date last accessed4 May 2023)

8. Han ZChen CChristiansen Aet alAntisense oligonucleotides increase SCN1A expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndromeSci Transl Med. 2020;12:eaaz6100DOI10.1126/scitranslmed.aaz6100

9. Hsiao JYuan TYTsai MSet alUpregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndromeEBioMedicine2016;9:25777. DOI: 10.1016/j.ebiom.2016.05.011

10. Tanenhaus AStowe TYoung Aet alCell-Selective adeno-associated virus-mediated SCN1A gene regulation therapy rescues mortality and seizure phenotypes in a Dravet syndrome mouse model and is well tolerated in nonhuman primates. Hum Gene Ther2022;33:57997DOI10.1089/hum.2022.037

11. Mora-Jimenez LValencia MSanchez-Carpintero Ret alTransfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestationsMol Ther Nucleic Acids2021;25:585602. DOI: 10.1016/j.omtn.2021.08.003

12. Niibori YLee SJMinassian BAHampson DRSexually divergent mortality and partial phenotypic rescue after gene therapy in a mouse model of Dravet syndromeHum Gene Ther2020;31:33951DOI10.1089/hum.2019.225

13. Tevard BiosciencesOur scienceAvailable athttps://tevard.com/#science (Date last accessed4 May 2023)

14. Colasante GLignani GBrusco Set alDCas9-based SCN1A gene activation restores inhibitory interneuron excitability and attenuates seizures in Dravet syndrome miceMol Ther2020;28:23553. DOI: 10.1016/j.ymthe.2019.08.018

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