Engineered Potassium Channel gene therapy for epilepsy

Epilepsy is common, affecting up to 1% of the population. Approximately 25% of people with epilepsy (150,000 in the UK alone) do not respond well to available medication. Such patients have an increased mortality, an increased rate of medical, surgical and psychiatric disease, experience social exclusion, and suffer from the side effects of medication. Drug-resistant epilepsy is especially common when seizures arise from a region of the cortex (grey matter). This can occur as a consequence of numerous processes such as developmental abnormalities, head injury, stroke and brain infections. In rare cases it is possible to remove this region surgically, with a high expectation of a cure, but more commonly such surgery is precluded by unacceptable risk to neighbouring or overlapping areas responsible for language, sensation, movement and other normal brain functions.

We recently showed that "calming down" neurons in an epilepsy focus was highly effective in a rat model of drug-resistant epilepsy. We achieved this by injecting a gene therapy treatment 'EKC' that leads to the overproduction of a normal human protein that regulates the excitability of neurons and their ability to talk to other neurons. The EKC treatment is safe and does not lead to inflammation, and we showed that the treatment was well tolerated and potentially amenable to clinical use in human epilepsy. This project will allow us to: (1) produce our EKC gene therapy treatment in a quality that is certified for use in humans, (2) to complete formal tests to show it is safe for use in the clinic, and (3) to carry out a first-in-human clinical trial of this gene therapy, to determine whether it is safe and well tolerated in a small group of patients with epilepsy.

We will initially trial this approach in patients who are undergoing assessment for epilepsy surgery, and in whom it is possible to remove a region of the brain that is responsible for seizures. Injection of the gene therapy into the seizure focus may spare them the need for definitive surgery. If the treatment fails we can remove the tissue at operation and study it in the laboratory. In the longer term, if this first trial is successful, we will test the effectiveness of the treatment in people who are not candidates for surgery, and for whom there is currently no hope for treatment.

Refractory epilepsy is a common, severe neurological disorder, for which there are limited treatment options.
We recently showed that overexpression of the human Kv1.1 potassium channel, encoded by KCNA1, suppresses seizures in a rat model of refractory focal neocortical epilepsy. The treatment was well tolerated and potentially amenable to clinical translation, but the construct used in that study was not optimal.
We have now refined our gene therapy construct to use a safer non-integrating backbone (pCCL), a synthetic cell-specific human promoter (CAMK2A), and a KCNA1 sequence engineered to remove the necessity for ADAR-dependent RNA editing. In a randomised blinded trial in a rodent model of focal neocortical epilepsy, we showed that this new engineered potassium channel (EKC) construct is highly effective in reducing seizure frequency, even when administered after epilepsy has become established.
We now apply for funding to produce GMP grade viral particles (M1), to carry out GLP safety and biodistribution studies at two time points (M2), and to carry out a first in human phase I/IIa clinical trial.
Our proposed initial study will be carried out in patients where the epileptic focus has been scheduled for removal. If successful, the treatment will subsequently be extended to patients for whom resection is not an option because of the proximity of the focus to eloquent cortex. Finally, if approved for use in humans, our approach will open the possibility of treatment for a range of disorders associated with excessive excitability of discrete neural networks (pain, Parkinson's, migraine).

This work is designed with the aim of offering a new treatment for people with refractory epilepsy for whom there is currently no effective treatment. Initially we will aim to treat people with refractory epilepsy who are scheduled for resective surgery. However if the trial planned here is successful our plan is to expand to begin to treat people for whom surgery is not an option. Because our gene therapy approach is not based on repairing a 'broken' gene, it will be available to the vast majority of people with epilepsy who do not carry a single causative genetic mutation.

Our aim is to provide a treatment that reverses the change in excitability seen in neurons that trigger seizures. By 'calming down' these neurons without silencing them entirely, we aim to reverse part of epileptogenesis and effectively to cure epilepsy. If successful this work would allow patients to avoid resective surgery, and maintain use of the affected region of the cortex.