A Network Approach to Gene Therapy for Refractory Epilepsies

Epilepsy is a serious and common neurological disorder affecting up to 1% of the global population, and approximately a third of affected people continue to have seizures despite optimal medication. People with drug-resistant epilepsy typically cannot drive, have difficulties holding down jobs, have a high risk of depression and suicide, and are at risk of falls, injury and even death during a seizure. At present, the most successful treatment for drug-resistant surgery is to remove the brain area where seizures arise. This is not without risk, frequently impacts on memory and learning, and is often only partially effective. This option is not even available for the majority of patients with drug-resistant epilepsy because the brain region where seizures start is necessary for movement, language, memory or vision, or because the seizures arise from a distributed network of brain areas. Such patients currently are condemned to a very poor quality of life.

The search for new drugs to treat epilepsy is unlikely to lead to a breakthrough. Despite many new medications developed in the last 30 years, the rate of drug resistance in epilepsy has not changed. The main limitation is that drugs affect the whole brain rather than just the neurons or neuronal circuits that trigger seizures. There is a real need for new treatments that work in a completely different manner.

We are the world's foremost group of scientists and clinicians committed to developing gene therapy for drug-resistant epilepsy. Epilepsy gene therapy works by using ultra-safe viruses to alter the genetic make-up of neurons in order to make them reluctant to fire or less likely to recruit down-stream neurons. However, to increase the chances of success in patients, we need to deepen our understanding of how seizures arise and spread through the brain, in order to identify where to target our treatments. Sometimes the best approach may be to treat not just the part of the brain with identifiable structural abnormalities or where early seizure activity can be detected, but also other parts of the brain which can stop seizures from spreading. New miniaturised electronic devices now allow us to accurately map where seizures start and how they spread with much greater precision than we had before, and this opens new possibilities for treatments. We have a portfolio of molecular tools that allow us to quieten down small, defined regions of the brain, so that we can determine which of these areas are best targeted for controlling seizures. We have, furthermore, identified new ways to suppress the abnormal firing of neurons as soon as the seizure starts, stopping it in its tracks. The proposed research brings forward these inter-connected themes, and we will validate progress not only in terms of suppressing seizures but also by looking at effects on memory, mood and behaviour.

By discovering new regions of the brain that can control seizures, we will greatly expand the number of patients who can benefit from gene therapies. Our project will broaden the repertoire of gene therapies available for epilepsy, and identify the strongest candidates to progress to clinical trials. As a team we have already pioneered a clinical trial scheduled to begin in the next year, and therefore have a proven track record of taking discoveries from the bench to the bedside in this underfunded area of biomedicine.

Drugs fail in many people with epilepsy, principally because they affect the whole brain. Surgery to destroy regions implicated in seizure generation is only suitable in very few patients. Gene therapy offers a rational alternative. Hitherto, it has relied upon treating a poorly defined epileptogenic focus, ignoring the emerging understanding of seizures as network phenomena.

Aim 1 is to identify the regions of the brain that are critical for the spread of seizures, using implanted Neuropixels probes, which allow the detection not only of local field potentials (which are dominated by synaptic currents) but also of action potentials across multiple brain regions.

Aim 2 is to determine whether acute manipulation of putative nodes of ictogenic networks, including piriform cortex and thalamic targets, is sufficient to block seizure propagation. As the project progresses new potential nodes arising from Aim 1 will be tested. Towards the end of the programme, we will determine which nodes or combinations should be treated to enhance treatment efficacy.

Aim 3 is to develop new tools optimised to stop the spread of seizures by potentiating potassium conductances. We will, in particular, focus on strategies for autoregulatory inhibition whereby a pathological glutamate elevation, as occurs in seizures, opens potassium channels. We will use human proteins to minimise obstacles to translation. We will also explore the potential of a secreted protein that upregulates potassium channels and has been implicated in both genetic and autoimmune epilepsy. These tools will be assessed in vitro and the most promising ones will be progressed to in vivo pre-clinical studies.

Throughout, we will use models of acute seizures and different aetiologies of epilepsy (hippocampal sclerosis, focal cortical dysplasia and inherited genetic mutations) to maximise clinical relevance. The work will feed into a translational pipeline that addresses an enormous health burden.