EEC 2026 | Emerging gene therapies for Dravet syndrome and other DEEs

So now we can investigate whether correcting a specific molecular abnormality actually changes both seizures and the neurodevelopmental disorder. For a lot of time we used to treat West syndrome and we’d give them corticosteroids, we’d give them vigabatrin, we would send them to surgery, and we would change that direction. And a few patients that we actually did, but the patients that we did were the ones that we could not identify any etiology for the West syndrome. So patients that had either a structural or patients that have a genetic disorder, those patients actually did not improve a lot when we controlled hypsarrhythmia or dysphasmus. And now we can say that we’re actually targeting that. Before that, we would have only one, probably one therapy that actually would work and would compete with corticosteroids and vigabatrin, that is surgery. So I knew that doing surgery very early on, we would enhance neuroplasticity and the patient would do better in a developmental way without the seizures. But now we can see that we can target this exact mechanism. Like I said, in Dravet syndrome, we have around 80 to 90% that SCNA1 loss of function mutations. So these patients have less sodium channel functioning, especially in the inhibitory neurons. And that’s why in these patients, when we block sodium channel, we actually make them worse. So it’s very common. These patients present with febrile seizures early on, the first or second year of life. And then someone at one time would think that, oh, because focal seizures, I’m going to give them carbamazepine or going to give them lamotrigine. And they actually get worse and actually get instants of life. That’s because this mutation especially targets inhibitory neurons. And that’s the thing, once you give them the sodium channel blocker, the developmental delay is probably very, very worse. So that’s probably going to get worse. So now we have a few medications that actually target the exact mutation. So these are a whole brand of new medications that we actually were seeing a lot in spinal muscular atrophy. And now it’s a most curable disease, right? We have here in Brazil, we’re probably going to have very soon a screening, a neonatal screening paid by the public health system for spinal muscular atrophy. So that’s amazing because it was a universally fatal disease that a patient would live on a few years and would have a very poor quality of life and we can almost cure it. So now in epilepsy, we’re seeing the transition of this oligosense, antisense oligonucleotides to the epilepsy, to the epilepsy bucket. Like I said, zorevunersen is the next big thing in epilepsy, I believe, is the next big thing in, in genetics in general. Because it, what zorevunersen does it improves the production of the SCN1A from the healthy copy of one that the patient has, because it’s a heterogenous mutation, mainly germinative, so the patients mainly do not inherit this mutation, so they have the mutation only in them. So it’s a medication that is intrathecal, like the first medications for spinal muscular atrophy, and this study that was published in the New England Journal of Medicine, I believe in June or between June and August, they showed that comparing to baseline, patients that had received the drug had over 90% of reduction in their seizure frequency. We know that it’s open-label and the patients may have, for a whole different reasons, their seizures may reduce, but that’s a population that if you work with them, you know, the Dravet syndrome does not have that kind of response, even to placebo. So we’re waiting very excitedly to see the Phase III trial, I believe it’s going to be called the EMPEROR, and see if the placebo response will stick to almost zero, which I believe is almost inversely with this patient’s response to placebo, while the arm receiving the zorevunersen will actually have a better response. In the European Congress, they actually presented a study that actually compared the developmental trajectories of patients with Dravet syndrome that received zorevunersen and those that are historical comparison. And they saw a very significant improvement in patients that had received the medication. So we have to make clear that these are patients that still are on open-label, but the doctors that actually worked with these patients, they showed pre- and post-administration video recordings of these patients, and something that we always see in these patients, but we actually do not pay a lot of attention, like ataxia or apraxia and so forth, actually did improve a lot. So these patients become very clumsy, they walk around, and they keep hitting things, hitting the door, and so forth. And before and after, it was like the brain would have a switch on. So the next few years are probably going to have this medication, and we have a lot of hope that’s going to be approved, and it’s probably going to have a very significant role in Dravet syndrome. I don’t think Dravet syndrome will be cured by this molecule, but it’s probably going to work a lot with fenfluramine, with stiripentol, and so forth, but maybe bexicaserin, as I said before. So that’s very exciting. Another approach is to actually put the corrected gene SCN1A in a viral vector and actually give them to the cell, to the neuron itself. So I believe the ETX101 is the medication that are actually one step further than zorevunersen because probably one or two administrations will give the functionally active SCN1A for the person for the rest of their life. So I believe that’s very encouraging and I believe that is going to get to the patients very soon. We cannot wait to see the results of the next trials.

And as I said before, Dravet syndrome is mainly a syndrome that affects SCN1A, but we also have a few patients that have SCN2A mutations. And we also have an antisense nucleotide that is being studied. Elsunersen is the medication that’s being studied for these patients. And they’re being studied mainly for patients with gain of function. So with SCN2A, it’s a different story. So these patients now have better response for sodium channel blockers and also they have intense current to the SCN2A receptors. So elsunersen actually blocks the expression of this of this gene and may improve the conduction in these neurons. I believe the name of the study is EMBRAVE, and they may be coming out, I believe, in the first trimester of 2027. And earlier results, I believe they were presented at the European Congress showed a 77% median reduction in seizure frequency in these patients. So that’s amazing. Once again, it’s a very refractory and very difficult to treat population. And I’m looking forward to see what their developmental marks will show, because they have also a lot of autistic traits, they have a lot of cognitive issues and so forth. And as with zorevunersen, elsunersen probably will get those better as well. So we will have to have better testing to see those changes in our patients because we usually do not apply so much to them because we’re always fighting to control the seizures. So I think that probably is going to have a very interesting role in the next couple of years. And I believe we can think that for the whole field and try to get that this possibility is more than amazing. It is extraordinary. It’s a treatment that actually preserves function or enhances function at the same time of treating seizures. Because for now, we still have to treat seizures and only seizures. And of course, seizures are very important for patients’ outcomes. But by that, we’re buying adverse events or buying even life-threatening adverse events, such as Stevens–Johnson syndrome. So I believe our test now will be to determine whether these therapies can deliver that promise that includes safety and also controlling seizures and improving development in a long-term basis.

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