Dravet syndrome gene therapy

One of the top google searches that brings people to my website is “Dravet syndrome gene therapy”.

I often review the Dravet syndrome pipeline (recently HERE and HERE, notably HERE), but so far we haven’t had yet any clinical trials with gene therapy in Dravet syndrome so those treatments are largely not in the reviews. Nevertheless, it is understandable that gene therapy is the most attractive therapy for people with Dravet syndrome. 

Here is a review of the gene therapies in development for treating Dravet syndrome, how each of them works, and when they are expected to start clinical trials.



In diseases like Dravet syndrome where the problem is that a copy of the gene is missing or not functional due to mutations, the desired therapy is one that can restore normal gene expression and therefore normal protein production. In other words, we need more protein.

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In the case of Dravet syndrome, the gene is SCN1A, and the protein that is needed is the neuronal sodium channel Nav1.1. As a result of mutations in the gene, the number of Nav1.1 channels at the neuronal surface is not sufficient, there is less sodium crossing the membrane, and the neuron cannot fire properly. The result is Dravet syndrome. 

One particularity of Dravet syndrome is that only one of the two copies of the SCN1A gene is affected, the second one is perfectly fine, so that second copy can serve as the supply for extra protein production. As you will see, the most advanced programs are exploiting this possibility.

Broadly speaking, there are two approaches to restore protein expression in Dravet syndrome: you either supply the cell with an extra healthy copy the gene, which will lead to more protein being produced, or you try to boost the expression of the healthy gene


(1) Supply a new copy of SCN1A 

When people think about “gene therapy”, the type of therapy they are thinking about is the one where the DNA of a virus gets replaced by the gene that the person needs, and that modified virus is used as a Trojan horse to infect cells and deliver them the therapeutic gene. 

If the SCN1A wasn’t so large that it cannot fit the most commonly used virus for gene therapy, the Adeno-Associated Virus (AAV), we would probably have clinical trials right now using AAV-based gene therapy for Dravet syndrome. A year ago I reviewed this problem in the article “big gene, small virus”.

However the large size of the gene has so far kept all gene therapy companies away from working with viral vectors for Dravet syndrome, and only academic groups are trying to push the current comfort zone of AAV gene therapy into a new era where we can use virus to deliver large genes. The good news is that there are multiple labs working on this, so there are multiple shots on goal:

||   Dravet Canada and the US Dravet Syndrome Foundation are supporting a gene therapy project at Toronto University that is developing a gene therapy for Dravet syndrome although not details are available on the approach used (virus or gene).

||  The Spain-France-Israel consortium CureDravet started a year ago to develop a gene therapy for Dravet syndrome using Adenovirus, a type of high-capacity virus that is large enough to contain the entire SCN1A gene (Strategy 1 in the figure). They are collaborating with Dravet Syndrome Foundation Spain and the Dravet Syndrome European Federation, and have also developed a close relationship with patient groups.

||  At UCL, the team of Rajvinder Karda is working on two approaches. One is to use another type of large-capacity virus, Lentivirus, to carry the SCN1A gene (Strategy 1 in the figure). The second approach uses two AAV virus, each containing half of the SCN1A gene, which are able to recreate the full channel once they co-infect the same cells (Strategy 3 in the figure). They have received the support from Dravet Syndrome UK and share updates with other interested patient groups.

All of these projects are in early preclinical stages, and they have not yet published a proof of concept in a Dravet syndromemouse model, which is an initial stage prior to advancing the treatments towards clinical trials. These programs are therefore all years away from clinical trial initiation, with no guarantee of succeeding.

dravet syndrome gene therapy


(2) Boost expression of SCN1A

Another strategy that has been used successfully in other diseases is to use small fragments of RNA (oligonucleotides) to boost the expression of a gene either without needing to add an external gene copy with a virus. This one is the strategy most advanced for Dravet syndrome.

||  The first program to be developed was OPK88001(previously CUR-1916) by OPKO Health. The therapy is a piece of oligonucleotide that binds to the DNA and removes an endogenous repressor of SCN1A (Strategy 3 in the figure). As a result, the good copy of SCN1A experiences much more transcription, leading to more mRNA and more Nav1.1 protein levels. The company expected to initiate clinical trials as early as in 2017, later announced to be in 2019, and as of February 2019 there are no news of when the program will be able to move into the clinic

||  2018 brought the good news that Stoke Therapeutics was developing an antisense oligonucleotide treatment to boost expression of SCN1A as well. This oligonucleotide binds to a form of mRNA and leads to an increase in the levels of mature mRNA and Nav1.1 protein (Strategy 4 in the figure). The company has shared preliminary data with efficacy in a mouse model and is planning to initiate clinical trials in 2020.  

||  Last, an academic group in Italy, with funding from CURE and the Dravet Syndrome European Federation,  is researching an alternative approach to boost production of Nav1.1 protein from the existing mRNA through another oligonucleotide approach (Strategy 4 in the figure).



(1) Questions to answer

Is overexpression of SCN1A bad? This is one important question that the field needs to answer so that we know if an excess of sodium channel as a result of the gene therapy could have negative consequences. This has been seen in some diseases where there are patients with duplication of the gene, for example in Rett syndrome where patients with Rett syndrome have a bad copy of MECP2 but there is also another disease caused by duplication of MECP2. In that case, increasing MECP2 levels too much with gene therapy would convert neurons from MECP2-deficient (Rett syndrome) into MECP2 duplication! 

There appears to be no negative consequences of mild overexpression of SCN1A but there has been no clear study how much increase is enough and how much is too much. This is one science gap important for gene therapy.

Other questions impact how to design a clinical trial with a gene therapy in Dravet syndrome. So far clinical trials measuring seizure frequency have been very successful, but a gene therapy is expected to improve the syndrome beyond just seizure frequency. Unfortunately, the field of Dravet syndrome is still immature when it comes to clinical outcome measure development and validation for non-seizure outcomes (for non-scientists in the audience: we don’t know how to quantify improvements of the disease in a clinical trial beyond seizures).

Also, all of these approaches are increasing the levels of Nav1.1, yet we don’t have any biomarker that could help us see what are the levels of functional or total Nav1.1 in patients. Imagine a clinical trial where a dose of the treatment is ineffective. If we don’t know if the dose had succeeded at restoring Nav1.1 levels, how would we interpret that trial? 

(2) New players needed

While it is exciting to see so many academic groups testing new forms of gene therapy for Dravet syndrome, I would like to see more companies in this space, in particular in the viral-mediated therapies. Beyond achieving the initial mouse proof of concept, the development of these therapies will face important challenges such as safety testing, scale up and manufacturing, clinical trial design able to measure non-seizure outcomes and biomarkers, and the massive cost of clinical trials. These challenges require the involvement of companies with the expertise and funding that can take these discoveries into the clinic and into the market, so the involvement of more companies in the gene therapy space for Dravet syndrome will be a necessary step as the pipeline progresses.

With Stoke now leading the development of oligonucleotide therapies for Dravet syndrome, it feels safe to think that the probabilities that we will have the first disease-modifying clinical trial for Dravet syndrome in 2020 is very high, and that an antisense therapy will reach the clinical trial stage. It is much less clear whether any of the current viral strategies will reach clinical trials since there is no corporate involvement. Antisense therapies and therapies with viral vectors have different advantages and disadvantages in the clinic. Because of that, I hope to see the antisense oligonucleotide approach from Stoke followed into the clinic by some company with a viral-mediated gene therapy approach, as it has happened in other fields such as SMA.



  • There are multiple gene therapy programs in development for Dravet syndrome including those that supply and extra copy of the SCN1A gene and those that boost expression from the healthy SCN1A gene copy.

  • Clinical trials are around the corner, with Stoke Therapeutics expecting to initiate clinical trials in 2020.

  • Just Stoke is not enough. New corporate players, and ideally some precompetitive collaboration around the common challenges of validating clinical outcome measures and biomarkers, are needed to maximize the success of gene therapies for Dravet syndrome.  


Do you know of any other gene therapy project that I missed? Let me know in the comments.

Ana Mingorance PhD