Lentiviral potassium channel expression to treat focal neocortical epilepsy

Epilepsy affects approximately 300,000 people in the UK, of whom about 100,000 do not respond to available medication. An especially severe form of drug-resistant epilepsy (focal neocortical epilepsy) often occurs when seizures arise from a small area of abnormal tissue in the brain. Because the rest of the brain is often intact, it should be possible to alter the excitability of neurons in the abnormal area to stop seizures arising or to terminate them when they occur. We have validated an experimental model of focal neocortical epilepsy and have done much ground-work to use modified viruses to change the expression of individual genes in neurons. We propose to reduce the excitability of neurons in the seizure focus, or alternatively to enhance the excitability of inhibitory neurons. Our work will build on preliminary data that we have obtained by studying the consequences of rare neurological disease caused by mutations of genes that encode ion channels, proteins that underlie the electrical signalling of individual neurons.

Focal neocortical epilepsy is among the most difficult forms of epilepsy to treat: it is very often refractory to available drugs, and the seizure focus is amenable to surgical resection in only a minority of cases. We have previously validated an experimental model of this disorder, which recapitulates its main features including continuous or near-continuous seizure activity and resistance to drugs that are effective in other epilepsy models. The seizures do however respond to focal drug delivery, showing that this disease is, in principle, treatable with more targeted methods of altering the excitability of neurons. We will capitalise on our complementary expertise in epileptology, cellular biophysics and molecular biology to test novel therapeutic strategies based on viral delivery of K+ channels into the seizure focus. We will express Kv1.1 and Kir2.1 (which we have previously studied in the context of neurological channelopathies) to lower the excitability of neurons in the seizure focus and/or reduce neurotransmitter release from their terminals. In parallel, we will also use promoters that are active in interneurons to drive the expression of a dominant-negative K+ channel mutant in interneurons, in order to raise their excitability and enhance neurotransmitter release from their terminals. The effectiveness of these strategies will be monitored by taking advantage of a new wireless video-EEG rodent telemetry facility that we have established.