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Development of a treatment for drug-resistant childhood epilepsy caused by potassium channel dysfunction.


Project Description

Gain-of-function mutations in the human gene KCNT1, which encodes the KNa1.1 sodium-activated potassium channel, cause severe childhood epilepsy that cannot be controlled by current medication. Attempts have been made to treat these patients with quinidine, an ion channel blocker, to reduce the over-activity of these channels. Unfortunately, in most cases this has been unsuccessful, with its well-known effects on the heart preventing sufficiently-high concentrations of quinidine being reached in the central nervous system. Novel inhibitors that are more potent and selective are therefore required.

The aim of this project is to identify compounds that have desired properties, and that could potentially be developed into a therapy for this unmet clinical need. Using computational and electrophysiological techniques, we have identified a range of novel inhibitors of the human KNa1.1 channel, with some lacking an effect on the cardiac hERG potassium channel. The project will involve studying the pharmacological properties of these and other compounds on recombinant KNa1.1 channels and on native ion channels in neurons and, if available, a mouse model of the disease. Site-directed mutagenesis will be used to replicate human epilepsy-causing mutations in expression constructs, whilst genome editing (CRISPR/Cas9) will be used to introduce the mutations in cultured neurons. Effects of mutations on currents and the pharmacological effects of the compounds will be assessed by patch clamp electrophysiology, whilst computational techniques (molecular docking) will be employed to understand the interaction between the compounds and the potassium channel protein structure. Should one become available, the pharmacology will be explored in a mouse model of this form of epilepsy, generated by introducing an equivalent genetic mutation.

Funding Notes

Applicants will need to secure funding for tuition fees, research and living costs,

References

Gertler et al (2018) KCNT1-Related Epilepsy. GeneReviews.
https://www.ncbi.nlm.nih.gov/books/NBK525917/

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

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