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Research Portfolio

GRANT TITLE:

Targeting epileptic seizures and cognitive comorbidities with a seizure-resistant KCC2 gene therapy

GRANT TYPE:

EMERGING LEADER FELLOWSHIP AWARD

grant amount:

£246,015 over 34 months, awarded in 2023

lead investigator:

Dr Amy Richardson

Co-Investigators:

-Supervisor: Professor Dimitri Kullmann (UCL)

institution:

University College London

Background

Approximately one-third of people with epilepsy do not achieve seizure-freedom with current medication. Cognitive problems, including with memory, are seen in around 50% of cases and present a major challenge for epilepsy treatment. Current treatments sometimes exacerbate these problems.

Too much electrical activity in the brain can lead to seizures. Usually, excessive activity is prevented by inhibitory ‘stop signals’ in the brain, which work by chloride ions moving into brain cells. At the start of epileptic electrical activity in the brain, chloride levels inside cells can build up so much that no more can enter, meaning this stop signal fails and can no longer keep neuronal excitation restrained. This results in electrical seizure activity spreading across the brain.

"Medications for epilepsy often focus on treating seizures, however, seizures are only part of the problem. Cognitive comorbidities such as impaired memory often occur in people with epilepsy and can also be a burden. In my project, I propose a new gene therapy treatment to try and target not only seizures but impaired memory to try an improve the overall lives of people with epilepsy.

The Study

We know that the KCC2 protein that removes chloride from neurons is decreased in epileptic brains, and that a reduced level of KCC2 is also linked to problems with memory. Therefore, increasing the amount of KCC2 protein should not only prevent this build-up of chloride in the neuron and fix the stop signal to protect against seizures, but hopefully also restore impaired memory associated with epilepsy.

Taking a gene therapy approach, this project aims to decrease epileptic seizures and associated impairments by increasing levels of KCC2. This research will test this new therapy in two models of epilepsy by recording the effect of KCC2 treatment on seizures and memory.

Significance

For patients with drug-resistant epilepsy, this research offers a potential long-term treatment option that may protect and restore cognitive function in addition to alleviating seizures. In comparison to traditional anti-seizure medications, this targeted treatment will have limited, if any, side-effects on the brain and body.

This research will also increase our knowledge on the importance of the KCC2 protein in providing effective inhibition against excessive brain activity and its role in learning and memory.