Glutamate-gated chloride channel treatment of epilepsy
Prof Dimitri Kullmann
University College London
Pharmacoresistant epilepsy affects approximately 0.3% of the population in developed countries and more than 200,000 people in the UK. Surgery can be used to stop seizures, but it carries risks to normal brain function.
We have developed a targeted gene therapy strategy based on a modified glutamate-gated chloride channel (eGlCl) expressed in excitatory neurons using a viral vector. eGluCl decreases neuronal excitability by opening in response to extrasynaptic glutamate when excitatory neurons fire excessively, without affecting normal brain function. We have demonstrated the efficacy of eGlCl in an acute chemoconvulsant model of evoked focal seizures and in a neocortical model of established epilepsy. It had no detectable behavioural side-effects.
We will adapt this study for clinical translation by: redesigning the construct; optimising delivery; and demonstrating efficacy and tolerability in a model of long-term limbic epilepsy. This will minimise the potential risks and attract investment for first inpatient clinical trials.