Presynaptic ion channel dysfunction in the forebrain

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Epilepsy and migraine are common and frequently disabling diseases that often do not respond to available medication. They both show a strong genetic influence, and most of the genes that have been identified to cause epilepsy or migraine encode proteins that mediate the flux of charged ions across the membranes of neurons. How abnormalities of these proteins cause episodic disturbances of brain function is not known. Although some progress has been made in documenting whether individual mutations increase or decrease the flux of ions, and under which conditions, the consequences for neuronal firing and signalling among neurons remain incompletely understood. Our work addresses these questions by applying advanced optical and electrical measurements to individual neurons in the brain.

Technical Summary

Idiopathic epilepsy and related paroxysmal disorders such as migraine represent an immense burden to the individual and to society. Ion channel dysfunction is thought to underlie much of the risk to the individual of developing these diseases. Monogenic channelopathies, manifesting as epilepsy, migraine or episodic ataxia, offer a unique window into the mechanisms by which altered ion channel function can give rise to paroxysmal CNS diseases. Although much is known about how disease-associated mutations affect the function of ion channels in heterologous expression, the consequences of these abnormalities for neuronal function in situ are poorly understood. The goal of the proposed work is to shed light on how mutations of two presynaptic ion channels (Kv1.1 and CaV2.1) affect action potential integration and neurotransmitter release in the hippocampus. We will apply advanced optical and electrophysiological methods, which we have recently optimised to examine mossy fibre signalling, in animal models of diseases caused by mutations of these channels. This work promises to shed light both on the normal roles of K+ and Ca2+ channels in the forebrain and how abnormalities in these channels can lead to seizures and other paroxysmal disturbances of brain function.

Publications

10 25 50
 
Description Engineered Potassium Channel gene therapy for epilepsy
Amount £2,200,000 (GBP)
Funding ID MR/R015333/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 04/2022
 
Description Innovator Award: Glutamate-gated chloride channel treatment of epilepsy
Amount £456,266 (GBP)
Funding ID 209807/Z/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2020
 
Description School of Pharmacy 
Organisation University College London
Department School of Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse mutants
Collaborator Contribution Expertise in ion channel recordings from presynaptic boutons
Impact Joint publication
Start Year 2009
 
Title COMBINED USE OF A VECTOR ENCODING A MODIFIED RECEPTOR AND ITS EXOGENOUS AGONIST IN THE TREATMENT OF SEIZURES 
Description The invention provides methods and materials for treating a seizure disorder such as epilepsy in a patient which employ a vector encoding a modified receptor, the so-called "DREADD" receptor being characterised by (i) a decreased responsiveness to its endogenous activating ligand (ii) a retained or enhanced responsiveness to an exogenous agonist. The modified receptor is expressed in neurons of a seizure focus in brain of the patient, and an exogenous agonist is administered which activates the modified receptor to reversibly alters the excitability of the neurons in the seizure focus leading to synaptic silencing or other inhibition. 
IP Reference WO2015136247 
Protection Patent application published
Year Protection Granted 2015
Licensed Yes
Impact We are seeking investment to take this to clinical trials
 
Company Name Sarentis 
Description Start-up founded by Dr Denise Barbut, New York 
Year Established 2015 
Impact Sarentis is currently seeking investment to take our gene therapy into clinical trials