Evaluating the efficacy of potassium channel inhibitors in KCNT1-associated epileptic disorders
ENDEAVOUR PROJECT GRANT
£141,236 over 36 months, awarded in 2022
Dr Jonathan Lippiat
University of Leeds
Genetic variations are a leading cause of epilepsy, particularly in those that encode proteins called ion channels. Ion channels regulate the passage of charged particles across the membranes of nerve cells and are responsible for electrical activity in the brain. One specific gene, called KCNT1, encodes a channel that regulates potassium ion movement, and epilepsy-causing genetic variants cause this potassium channel to be more active than it should, letting too much potassium across the membrane. This epilepsy is rare, with about 300 genetic diagnoses worldwide so far, but there are likely to be thousands in total. KCNT1-associated epilepsy can be severe, causing several seizures per day and some affected children are unable to speak or walk. Unfortunately, current epilepsy medicines are not effective in KCNT1-associated epilepsy, so new treatments are urgently needed.
"We hope that our research can make advances towards finding a way to treat KCNT1 epilepsy. At the moment, there is very little out there that’s effective to give children who have this debilitating condition. A chemical that reverses the problem at its source could be the solution.Dr Jonathan Lippiat
Because genetic variants increase potassium channel activity, one way that a drug could work is by reducing potassium pathways. Using computer programmes that predict which chemicals interact with the potassium channel protein, Dr Lippiat’s team have been able to discover some inhibitors. They must now see if these chemicals can suppress brain activity and have the potential to be developed into a treatment for KCNT1 epilepsy. The team will do so in an experimental model of epilepsy that contains a KCNT1 variant that causes severe epilepsy in affected children. They will use imaging techniques to detect whether the KCNT1-inhibiting chemicals reduce electrical activity in specific brain regions, before assessing the ability of the chemicals to prevent seizures and other symptoms associated with KCNT1 epilepsy. Dr Lippiat’s team will then be in a position to work with pharmaceutical experts to develop promising chemicals into a treatment.
If successful, this research will demonstrate the potential for computer-assisted drug discovery with ion channels, which could be used to find treatments for many other types of epilepsy. Upon completing the research, the team will have a good understanding of the properties of chemicals likely to be effective KCNT1 inhibitors and treat epilepsy. They will then be able to work with drug development and pharmaceutical specialists in our research network and KCNT1 Epilepsy Foundation to continue to move the research forward towards the clinic and people living with this difficult to treat conditions.