Novel Therapies in Development for Dravet Syndrome

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Joseph Sullivan, MD: We’re still looking at seizures, and we’re maybe seeing some of these behavior and executive improvements with fenfluramine. But we really need something beyond seizure control, right? We’ve got to try to get at that underlying SCN1A haploinsufficiency. And it’s exciting. I’m sure you’re as excited as I am to be involved with some of these other clinical trials that have either started or will be starting soon that are trying to get at some underlying disease-modifying approaches. It almost seems like science fiction to me, in the sense that 5 years ago I probably put my foot in my mouth and said to some families, “I just don’t see gene therapy in my lifetime.” I was having a hard time wrapping my head around what, at least I thought, was the conventional approach of gene editing. 

Elaine C. Wirrell, MD: That’s why we have these super-bright PhD people who have an interest in this area.

Joseph Sullivan, MD: Exactly.

Elaine C. Wirrell, MD: I think that’s been very exciting to see develop.

Joseph Sullivan, MD: Exactly, and it’s exciting to think that it could extend to other pediatric epilepsy genetic diagnoses, not just Dravet syndrome. But right now, there’s a lot of focus on Dravet syndrome, and that’s obviously why we’re here. Maybe you could explain, for me and for our audience, this technique that’s the antisense oligonucleotide that’s in phase 1/2 clinical trial.

Elaine C. Wirrell, MD: Sure. What that is, it targets mRNA. In Dravet syndrome what happens is the pathogenic variant leads to degradation, nonsense mediated decay of this mRNA, so it can’t function to then make protein. What this antisense oligonucleotide does is it kind of forms this bridge and it prevents the degradation from happening, and so it restores normal NaV1.1 protein. It resolves that haploinsufficiency you see in Dravet syndrome and restores normal levels of protein. So with that, there’s a lot of excitement that that then targets the underlying pathogenesis. The hope is that it will not only improve seizures but also reduce the risk of SUDEP [sudden unexpected death in epilepsy], and it looks, at least in animal studies, that that might occur, and may also improve many of the other comorbidities, sort of attenuate the developmental concerns that we see, improve gait issues, behavior. So it’s very exciting.

Joseph Sullivan, MD: Absolutely. I get some questions from families who say, “Well, does my child’s mutation qualify?” This is not going in and fixing the variant your child may have, but rather is taking advantage of that working nonmutated copy, to basically tell it to do more, or to use the products of its labor in a more effective way that ultimately translates into, as you said, increased expression of that NaV1.1 channel. And in those animal models, it has done exactly that. When they look at the expression not only of the messenger RNA, but of the percentage increase in the sodium channel, it approximates that of an individual, or of a mouse in this case, who has two working copies of the SCN1A gene. Then there’s another, also equally brilliant, approach to use an adeno-associated virus, AAV technology, which conventionally has sometimes been used to insert the actual gene into the genome so that it does “fix” them. But the SCN1A gene is too large to be packaged in that virus.

So Encoded Therapeutics, [Inc] has devised this approach where a genetic promoter essentially binds to the working, nonmutated allele, the working SCN1A copy, and effectively tells it to produce more of this messenger RNA, which can then be translated into hopefully a working sodium channel, the NaV1.1 protein. It’s the same sort of end result, but a different way of getting there. Both of these approaches are either in early clinical trial or are going into clinical trial very soon, and so it is exciting to think about not only FDA-approved medications to treat seizures, but something that could get at the root cause. I think there’s a lot of interest, certainly from us as clinicians and our colleagues, but even more interest on the part of the patient community, because this is what they’ve been asking for, for so long.

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Transcript Edited for Clarity