Introduction

Epilepsy is treated today with anti-seizure medications and in select cases, with surgery.  Although there are over 25 possible anti-seizure drugs, approximately 30% of patients with epilepsy do not respond to drug treatment and those who do, frequently endure adverse side effects.  Thus, there is an urgency to find better therapies.  One potential future strategy is gene therapy for epilepsy (see other strategies, Noncoding RNAs: diagnosis/cure for epilepsy?).

Gene therapy for diseases other than epilepsy have shown success (https://learn.genetics.utah.edu/ content/genetherapy/success/).  These diseases include immune deficiency diseases, hereditary blindness, hemophila and Parkinson’s disease.  In the future, epilepsy may also benefit from gene therapy.   This blog is based on several excellent reviews (see References below) that describe the reality of this future therapy.

What is gene therapy?

Gene therapy is a special technique whereby a gene carried by a vector is injected into a patient.  The selected gene is one that would replace, optimize or inhibit the disease-producing gene.  The vector can be viral or synthetic.  Viral vectors are either adeno-associated viruses, lentiviruses or a herpes simplex viruses.  These viruses are modified so that they can no longer divide and infect.  Therefore, they serve only as carriers.  Synthetic vectors are non viral vectors such as lipids and polymers.  Although not as efficient as viral vectors, synthetic vectors get into the brain readily and are easily manufactured.

What genes are important in epilepsy?

Researchers have identified several genes that influence different aspects of epilepsy.  Genes identified thus far are

a)  membrane channels that conduct ions e.g. sodium and potassium;

b)  receptors at the junction of nerves e.g. the NMDA receptor;

c)  neuromodulators influencing nerve excitability e.g. neuropeptide Y;

d)  genes involved in influencing DNA function e.g. adenosine and associated enzyme, adenosine kinase.

Ideally, gene therapy for epilepsy has three areas of focus.  This includes gene therapy for prevention of  disease initiation, eradication of seizures and amelioration of those brain areas subsequently changed by epilepsy.  It is thought that seizure inhibition is likely to be the first successful target for gene therapy.

Assessment of gene therapy

Animal Models

Gene therapy has been primarily investigated in animal (mouse, rat) models of epilepsy.  Most models evaluate one aspect of epilepsy.  Accordingly, there exists the PTZ model in which an injection of convulsant-inducing pentylenetetrazol causes generalized seizures.  This acute model has been helpful in screening for anti-convulsant drugs.  Another model (termed latent) requires a waiting period for seizure development following a particular insult (pilocarpine, kainic acid).  The initial phase is thought to mimic known injuries e.g. stroke, fever, trauma in man.  This type of model has considerable value in that the initiating changes, the seizures and associated cognitive changes may be investigated.  There also exist models of spontaneous seizures. 

Promising results in animal models

Ion Channels – target of gene therapy

Most of the current anti-seizure drugs block the defective sodium channel located on nerves. Drug-induced inhibition reduces the nerve impulse and dampens the unwanted excitability of the seizure.  Conversely, super activation of the potassium channel has a similar effect.  Therefore, gene therapy to correct defective sodium and potassium channels is reasonable. 

In mouse models analogous to infant epilepsies, several studies showed that gene therapy for the sodium channel inhibited seizures and improved other brain deficiencies.   In two rat models of epilepsy (focal neocortical and temporal lobe), gene therapy of a modified potassium channel effectively suppressed seizures.

Neurotransmitter Receptors – target of gene therapy

Nerves communicate with one another via release of small molecules called neurotransmitters that act on specific receptors.  Two neurotransmitters of interest in epilepsy are gamma-aminobutyric acid (GABA)  and N-methyl-D-aspartic acid (NMDA).  The former acts on its receptor to inhibit nerve activity and the latter acts on its receptor to enhance it.  Thus, these neurotransmitter receptors are potential gene therapy targets. 

Enhancing the number and/or activity of  the receptors stimulated by GABA  decreases seizure activity in animal models.  Conversely, modification of the receptors responding to the excitatory stimulation of NMDA attenuates seizures in animal models. 

Neuromodulators – target of gene therapy

There exist an abundance of neuromodulators that not only influence the extent of neuronal traffic but also affect nerve cell integrity.  Neuromodulators are thought to play a role in collateral changes with epilepsy.  

Several modulators of nerve excitability such as neuropeptide Y (NPY), dynorphin, fibroblast growth factor 2, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor have been evaluated in animal models.  Vector carriers varied from adenovirus (NPY) to synthetic carriers (glial cell neurotrophin) injected directly into the brain.  Depending on the models, diminished seizures or reduced abnormal nerve cell growth  was reported. The effects were stable for months to one year.

DNA modulators – target of gene therapy

Adenosine and its metabolic enzyme, adenosine kinase play a role in epilepsy.  An increase in the enzyme activity results in a decline in the concentration of adenosine.  Adenosine is an important player in gene expression.  Hence, it influences what genes are “on” and which are “off”.  Patients with epilepsy are deficient in adenosine.  In rat models, implantation of a synthetic vector-releasing adenosine into the epileptic brain beneficially influences gene expression, retards abnormal neuronal growth and decreases seizure frequency.

Clinical trial using gene therapy

There is one clinical trial in progress to evaluate the safety and efficacy of gene therapy in epilepsy. This is the ENDEAVOR trial.  Its protocol is to test adenoviral-delivered sodium channel gene to infants 6-36 months with Dravet Syndrome.  Dravet syndrome is a severe form of epilepsy with seizures, mental and growth retardation and sudden death potential.  Many with Dravet Syndrome have a single mutation in the sodium channel making gene therapy possible.  This trial will evaluate the safety and efficacy of ETX101 (vector-promoter-gene complex) injected into a cerebral ventricle (https://clinicaltrials.gov/ct2/show/NCT05419492).

Challenges

Gene therapy has the potential to cure some forms of epilepsy. The ENDEAVER trial is one to follow. 

However, there remain considerable challenges to overcome.  These challenges include the complexity of genetic mutations.   Although there are a few epilepsies tied to one gene,  most epilepsies involve multiple genes..  Even when only one gene is identified, there is no guarantee that the defective gene acts the same way in each patient with that particular type of epilepsy.  Vector selection is also a challenge since the vector must deliver the gene to the correct cell type, gain access to the brain when given intravenously, persist for an adequate amount of time and not induce an unwanted immunological response.  Much of this has been and continues to be resolved in animal models, but gene therapy still awaits well-designed safety and efficacy studies in man.

References

Balestrini S, SisodiyaSM. Pharmacogenomics in epilepsy.  Neuroscience Letters 667: 27–39, 2018.

Bouza AA, Isom LL. Chapter 14: Voltage-gated sodium channel β subunits and their related diseases. Handb Exp Pharmacol. 246:   423–450, 2018.

Thakran S et al., Genetic Landscape of Common Epilepsies:  Advancing towards Precision in Treatment Int. J. Mol. Sci. 21: 7784, 2020.

Zhang L, Wang Y. Gene therapy in epilepsy Biomedicine & Pharmacotherapy 143: 112075, 2021.