The Potential of Gene Therapy to Treat SCN1A-Positive Epilepsy

January 22, 2020
Matt Hoffman
Matt Hoffman

Matt Hoffman, Senior Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017, and previously wrote for its sister publication, HCPLive. Follow him on Twitter @byMattHoffman or email him at

The medical director of the Comprehensive Epilepsy Clinic at Nicklaus Children’s Hospital shared his insight into the potential of using an SCN1A-targeted adeno-associated viral vector-based gene therapy in epilepsy.

Ian Miller, MD

Due to recent successes in a number of rare genetic conditions with gene therapies, more interest has grown in the possibility of using adeno-associated viral vector (AAV) based gene therapy for SCN1A-positive epilepsy.

Mutations in the SCN1A gene can result in a number of seizure disorders, most commonly Dravet syndrome—nearly 90% of patients have an SCN1A mutation. At the 73rd annual meeting of the American Epilepsy Society (AES), December 6-10, 2019, in Baltimore, Maryland, data presented from a mouse model showed that a GABA-selective AAV vector significantly reduced hyperthermic seizures, decreased the frequency and duration of electrographic seizures, and significantly reduced the risk for SUDEP by 89% when administered to SCN1A+/− mice.1

Additionally, a group of investigators including Ian Miller, MD, medical director, Comprehensive Epilepsy Clinic at Nicklaus Children’s Hospital, and colleagues, presented a novel approach to AAV-based gene therapy for SCN1A-positive epilepsy.2 He explained that a challenge with current approaches is that the viral vectors can only accommodate small genes, not large, complex ones like SCN1A.

To find out more, NeurologyLive spoke with Miller at length, inquiring about his and his colleagues’ work into this subject.

NeurologyLive: Could you explain the work you and your colleagues are doing and how this therapy works?

Ian Miller, MD: I'm one of the clinical team members, and a lot of the work—all of the work so far—has been preclinical, on the basic science side, so they can speak to it way more than I can. However, the encoded concept makes a ton of sense from a clinical standpoint. It has a lot of advantages.

The gist of it is that they're taking a well-established AAV gene delivery platform—and the fact that this well-established helps us already kind of gain certainty about safety and tolerability because it's been used in humans before—and delivering a mechanism to increase SCN1A expression. SCN1A expression is the way that I see it, rather than increasing SCN1A copies because they don't actually deliver any copies. They deliver a kind of a custom regulatory element that will select for the interneurons—the GABAergic interneurons, which are inhibitory, which means that you won't have side effects in other cells. Then, you have additional selectivity in terms of using an engineered transcription factor which will preferentially express the SCN1A protein by creating a protein that upregulates SCN1A expression.

Unlike the traditional model or the default mental picture that people have of taking an extra copy of SCN1A and putting it into the nucleus somewhere, the approach here is actually putting something into the nucleus, which when translated, will increase transcription of SCN1A. It's a very regulation-centric model rather than a copy number model. That approach brings down the size of the payload that's needed to induce the effect. It makes it possible to deliver this well-characterized, relatively safe virus and makes it really exciting for patients.

Will this be for Dravet syndrome, or will other epilepsies benefit from this regulation-centric model?

I prefer the term SCN1A-related epilepsy to Dravet because Dravet includes other genes. Ninety percent of Dravet syndrome is caused by SCN1A mutations, and this is only for SCN1A—so it’s really SCN1A-related epilepsy. The other challenge that comes up with that terminology is that before the natural history of the patient has really declared itself, you don't know whether they will have Dravet or whether they will have a severity that's somewhere else on the GEFS+ spectrum and so SCN1A- related epilepsy really captures all of it. Anybody who has that, even if they're young enough that Dravet a is uncertain, it's not important as long as SCN1A is the cause, then this is an appropriate therapy.

Anything to note for your peers?

The thing that's really important to understand about the therapy is that because it's genetic, it has the ability to address parts of cognitive function that no other treatment that's available today can even hope to address—that's the direct effect of gene dysfunction on education, learning, and cognition. We have treatments that can help learning and cognition because seizures bring it down, and so we'll stop the seizures and we'll allow that to flip back up and hopefully improve. We have medications that are less sedating and have fewer intoxication effects on cognition and behavior, but this is the only thing that can touch the direct genetic effect on cognition and behavior that other conventional anticonvulsant medications can’t.

Transcript edited for clarity.


1. Young AN, Tanenhaus A, Belle A, et al. A GABA-selective AAV vector upregulates endogenous SCN1A expression and reverses multiple phenotypes in a mouse model of Dravet syndrome. Presented at: AES 2019; December 6—10, 2019; Baltimore, MD. Abst. 3.1.

2. Segal E, Miller I, Perry MS, et al. Proposed designed for a natural history study of SCN1A-positive (SCN1A+) early-onset epilepsy. Presented at: AES 2019; December 6—10, 2019; Baltimore, MD. Abst. 3.085.

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