Investigating the target engagement of ion channels in human peripheral nerve by drugs

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

Abstract

Ion channels are proteins in nerves cells that control their excitability and information transmission. Several lines of evidence indicate that novel drugs that modulate these ion channels could work as potent pain killers. So far it has been impossible to non-invasively study the action of drugs on these ion channels in humans and this has hampered the transition from preclinical studies on animals to early clinical trials in humans volunteers. This proposed research project aims to develop a platform technology that would eliminate this bottleneck. It uses a semi-automated computer system that administers small, painless electrical impulses in different configurations to a nerve of the hand. The responses recorded from muscle or a finger inform us about the activity of various ion channels in motor or sensory nerve fibres, respectively. To validate the method we are interested to see whether different drugs that are known to affect specific ion channels evoke distinct changes of ion channels and thereby nerve responses that we can pick up with the new technique. This information is important for several critical steps of drug discovery programs. First, it allows to see whether drug effects are specific. Second, one can also see what percentage of ion channels are affected at a given dose. This will facilitate the crucial step of appropriate dose finding when drugs move from animal studies to human investigations. Furthermore, it is not uncommon that animal studies suggest pain relieving effects, whereas the same compound appears to have no such effect in patients. This can happen because the drug is not effectively modulating the ion channel in humans or, alternatively, the ion channel is modulated, but the ion channel is not important for pain perception in humans. This puzzle can only be answered by direct measurement of the drug effect on the ion channel ? or to say it in the words of an engineer ? to measure is to know. This is currently not possible, but the technology we wish to develop, holds the promise to this for the first time.

Technical Summary

Increases in peripheral nerve excitability are the cause of many forms of pain. Drugs modulating ion channels in peripheral nerve are therefore a prime target for novel analgesics. However, a major bottleneck in drug discovery for these compounds is the lack of translational biomarkers. The proposed project will employ the techniques of nerve excitability testing that is used in animal models in vivo and in vitro and that can be applied to humans to human volunteers and patients. The aim is to conduct a series of proof of concept studies in order to establish this technique as the first translational biomarker for ion channel function in clinical trial programs including dose finding studies. We will use available reference compounds lamotrigine, lacosamide, ivabradine or retigabine in normal volunteers to modulate sodium or potassium channels or the Ih current, respectively to see whether this technique affects distinct nerve excitability parameters. After successful completion this project is likely to sustain its future funding through pharmacutical companies developing novel ion channel modulators

Publications

10 25 50
 
Description Drug Disovery Fund
Amount £50,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 01/2012
 
Description Studentship
Amount £30,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 09/2012 
End 09/2015
 
Title Analysis of novel sodium channel antagonists 
Description In collaboration with Erik Arstad we have analysed novel sodium channel antagonists using several in vitro nerve excitability parameters 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This work has just been started 
 
Description Neusentis 
Organisation Pfizer Ltd
Department Neusentis Pfizer
Country United Kingdom 
Sector Private 
PI Contribution UK drug company
Collaborator Contribution Collaborating on early clinical and preclinical development of novel analgesic drugs that atrget voltage gated sodium channels and neurotrophins
Impact Currently studying drugs
Start Year 2013
 
Title QTRAC CBZ 
Description Development of a translational neurophysiological biomarker for the assessment of the target engagement of ion channels by drugs. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Better translation from pre-clinical to early clinical trials 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=9799