Engineered Potassium Channel gene therapy for epilepsy

Lead Research Organisation: University College London
Department Name: Institute of Neurology


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.

Technical Summary

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).

Planned Impact

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.


10 25 50
Description Appointed to board of Trustees for Epilepsy Research UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Description UCL Celebrates the 3Rs
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Description Collaboration with KCL for GMP synthesis of Lentiviral particles for gene therapy 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution This research has involve close work with our partners at Kings College, led by Farzin Farzaneh. We are developing new approaches to manufacture and validate the lentiviral particles, which will support clinical trials. We are leading on the safety and validation steps.
Collaborator Contribution The KCL team is leading on the manufacturing process.
Impact The main output will be the new manufacturing process for the lentiviral particles. We are working closely with the MHRA to ensure the approach is suitable for clinical trials. The added value is that the KCL team has made three batches of viral particles instead of just one, as originally planned, in order to refine the manufacturing process.
Start Year 2018
Description The invention provides methods and materials for treating a seizure disorder such as epilepsy in a patient which employ a vector encoding a modified receptor, the so-called "DREADD" receptor being characterised by (i) a decreased responsiveness to its endogenous activating ligand (ii) a retained or enhanced responsiveness to an exogenous agonist. The modified receptor is expressed in neurons of a seizure focus in brain of the patient, and an exogenous agonist is administered which activates the modified receptor to reversibly alters the excitability of the neurons in the seizure focus leading to synaptic silencing or other inhibition. 
IP Reference US2016375097 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact This licencing is part of a portfolio of approaches to developing gene therapy to treat epilepsy
Description The invention provides expression vectors, nucleic acids, vector particles and methods of treatment involving these vector particles, comprising an engineered KCNA 1 gene encoding an edited Kv1.1 potassium channel, as well as methods of confirming the presence of engineered KCNA 1 mRNA in a cell. The features of the engineered KCNA 1 gene combine to advantageously enhance the translation and activity of the Kv1.1 protein and improve detection of KCNA 1 gene expression in a cell and can be used for example in the treatment of epilepsy and similar neurological disorders. 
IP Reference WO2018229254 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact This patent is helping support our award to translate our gene therapy to a first in human clinical trial
Description Royal Society Summer festival presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a summer science 'lates' which meant running a both with a hands on activity for people attending the Royal Society Summer Science Festival. We presented an origami hands-on demonstration of how gene therapy uses viral shells to carry instructions for making healthy genes. The event was very well attended with over 3000 at the Royal society, and my personal booth (going by how many sheets of origami paper we gave out) had over 100 visitors, mostly from the general public but also some schools and university students.
Year(s) Of Engagement Activity 2018