Gene Therapy in Epilepsy: The Current Pipeline

Recovery in Hospital

Our previous article discussed some of the challenges associated with gene therapy for the treatment of epilepsy, such as delivery, therapeutic goals, and risks.

We now take a closer look at the leading projects aiming towards the use of gene therapy for the treatment of epilepsy.

For many gene therapy projects, the ideal therapeutic aim is to eliminate the disease once and forever. However, this is a good time to remind ourselves that the therapeutic aim of a gene therapy-based epilepsy treatment may not (or cannot) necessarily be an outright cure.

For many patients, especially those who are drug resistant, or for whom surgery is not a viable option, a successful gene therapy approach may manifest itself as a return to drug responsiveness, or a reduction of seizure frequency or seizure severity.

Furthermore, even among those eligible for surgery, the avoidance of major resective surgery may be a therapeutic result which is deemed a success by patients and their caregivers.

We should keep these goals in mind as we delve into the details.


Gene Therapy Candidates

According to GlobalData, there are two active programs involving gene therapies for the treatment of epilepsy. There is also a third program, which is labeled as inactive. All three programs are described below.

BNP-TLE (Asklepios) – North Carolina-based Asklepios  is developing a series of gene therapies using their proprietary Biological Nano Particles (BNP) technology. The BNP platform can be used for the delivery of a variety of genes, as demonstrated by the company’s pipeline, which has programs in muscular dystrophy, hemophilia B, and other conditions including epilepsy.

BNP-TLE is a gene therapy approach using BNP particles to deliver a gene encoding for galanin as a treatment for temporal lobe epilepsy (TLE).

Galanin is a neuropeptide involved in many biological functions, such as sleep and mood regulation, blood pressure regulation, and others. Galanin is relevant for epilepsy because it is an inhibitor of glutamate release, which increases seizure threshold.

In fact, galanin analogs have been described which have some anti-convulsant activity.  It stands to reason that a gene able to regulate the synthesis and release of a galanin receptor agonist could be a viable approach.


NPY/Y2 (CombiGene) – Based in Sweden, CombiGene is taking a more sophisticated approach to gene therapy for epilepsy.  The company proposes to deliver genes encoding two proteins: Neuropeptide Y (NPY) and its receptor Y2.

NPY is a 36-amino acid peptide neurotransmitter, which is believed to have multiple biological functions, such as regulation of anxiety and stress, reducing pain perception, and regulating blood pressure.

In a large number of in vitro and in vivo studies it has been found that NPY inhibits glutamate release, thereby controlling excitability in the hippocampus of the brain. Exploring this mechanism further, several studies in epilepsy models have demonstrated that NPY reduces seizure susceptibility in the brain, showing that NPY has both anti-excitatory and anti-epileptogenic properties. Interestingly, the anti-epileptic effects of NPY in temporal lobe epilepsies have been shown to be mediated predominantly via the Y2 receptors.

This suggests that increasing the expression of both proteins (Neuropeptide Y and Y2 receptors) will have a synergistic anti-epileptic effect in epilepsy. Studies with human tissue samples from epileptic patients have demonstrated that NPY suppress seizures by interacting with Y2 receptors, thereby supporting the idea of promoting both NPY production and Y2 upregulation via gene therapy. 

rAAV-NPY (Neurologix) – Before filing for bankruptcy in 2012, Neurologix was making excellent progress in the development of a neuropeptide Y-based gene therapy for epilepsy.

In rodents, the Neurologix candidate achieved a 50% reduction in seizure frequency, a 45% reduction in seizure duration, and a 70% blockage of seizure progression, without adverse effects or safety issues. An IND was scheduled to be submitted to the FDA in 2005

Thus, while the company was unable to advance their program, it did demonstrate that NPY-based gene therapy can be effective and safe in Preclinical animal models.


Other Candidates

A number of other genes and vectors have been described in the literature for the potential treatment of epilepsy. These have been reviewed in an excellent article by Michele Simonato of the University of Ferrara in Italy. In fact, the article makes several important points regarding the potential for gene therapy in epilepsy.

First, as Simonato points out, gene therapy may be the only viable approach towards the development of a truly anti-epileptogenic therapy. No other approach known today can prevent the development of epilepsy, but certain gene therapies can theoretically do this.

Second, there is a therapeutic gap between drugs/devices and surgery. In other words, there is a substantial population of patients for whom traditional drugs are not sufficiently effective, and for whom devices such as deep brain stimulation and/or surgery may be undesired or even contraindicated. A gene therapy approach could fill this gap in the treatment continuum, especially in epilepsy subtypes which are notoriously resistant to standard therapies.

Thirdly, our collective understanding of gene therapy delivery via viral vectors is far better than it once was. So while safety trials are obviously required, we are far more confident that any clinical failures are unlikely to be caused by the vectors themselves.


The first paper discussing gene therapy for epilepsy was published in 2004. Since then, a great deal of effort has been made to a) understand which proteins & genes may confer a desired clinical benefit, b) which vectors are most likely to be both safe and effective and efficient in delivering genes to the key areas in the brain, and c) understanding what clinical endpoints are actually possible with a gene therapy approach.

Given the unmet need which still exists across multiple forms of epilepsy, it is very likely that one or more of the programs described above will make it into clinical trials in the near-term.

There is still some debate in the literature regarding which genes should be used for epilepsy, as the Simonato review clearly suggests. However, it appears that NPY (perhaps with Y2) and galanin approaches will break through and enter the clinic first. Even if this is the case, many more questions remain unanswered, and can only be answered through additional studies.

What is abundantly clear is that gene therapy has clearly moved out of the realm of the exotic and into mainstream drug development in epilepsy. And, it is an area which warrants closer attention as additional study results are published.

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