Attendees will learn about the role of sodium channels in various pain phenotypes and the application of modern technologies to develop new, non-opioid pain therapies.
This webinar will feature an academic case study on NaV1.9 as a drug target by Professor David Bulmer (University of Cambridge). The webinar will also include a presentation by Metrion CSO, Dr. Eddy Stevens with an overview of Metrion’s newly developed NaV1.9 screening assays.
The Voltage-Gated Sodium Channel NaV1.9 a Selective Target for Analgesic Drug DiscoveryProfessor David Bulmer PhD, Group Leader University Associate Professor, University of CambridgeThe development of effective non-opioid pain killers remains an area of significant unmet clinical need and one of the great challenges for drug discovery. One approach to this problem has been to target the ion channels responsible for the activation of pain sensing neurons in disease states thereby blocking the transmission of pain from the periphery to the central nervous system in a manner analogous to the use of local anaesthetics. These drugs inhibit the activation of voltage gated sodium channels (NaV) to prevent action potential firing, and while highly effective are restricted in use and delivery as their non-selective inhibition of NaV channels may lead to cardiorespiratory paralysis. These problems can be avoided thanks to the tissue specificity of NaV subtypes. With drugs highly selective for NaV channels expressed on sensory nerves such as NaV1.8 demonstrating analgesia in the absence of cardiorespiratory side effects highlighting the tremendous potential offered by sub-type selective NaV blockers1. Alongside its more well studied siblings the voltage gated sodium channel subtype NaV1.9 is selectively expressed within the nociceptive population of sensory neurons where it is responsible for nociceptor sensitisation due to its lower voltage threshold to activation and persistent sodium current compared to other NaV subtypes2. These biophysical properties and selective distribution make NaV1.9 an ideal analgesic drug target. Here we review the data showing the critical role for NaV 1.9 in the transmission of pain signalling in disease states, and inhibitory effects on patient tissue driven nociception3. 1 Jones et al N Engl J Med (2023) 389 393-405. 2 Bennett et al Physiol Rev (2019) 99 1079 –1151. 3 Hockley et al Pain (2014) 155 1962-75. | Development of a High-throughput Automated Electrophysiology Assay for NaV1Eddy Stevens, CSO, Metrion BiosciencesThe voltage-gated sodium channels, Nav1.7, Nav1.8 and Nav1.9 underlie action potentials in nociceptors, where Nav1.9 controls threshold of firing. Voltage-gated sodium channels are an important target for the development of novel treatments for pain. where there has been extensive activity across biotech/pharmaceutical industry focusing on Nav1.7 and Nav1.8. Nav1.9 is of particular interest as a therapeutic target for pain due to its nociceptor-specific expression and the genetic association of SCN11A with human pain insensitivity disorders. Nav1.9 has been difficult to prosecute as a pain target due to technical challenges in achieving reliable expression of Nav1.9 in heterologous systems. Metrion has generated a robust monoclonal cell line expressing hNav1.9 in CHO cells which has been validated using both manual whole-cell patch clamp and automated patch clamp platforms (QPatch48, Sophion Biosciences). Data will be presented from a high-throughput Nav1.9 assay using Qube384 (Sophion Biosciences). |
Professor David Bulmer PhDGroup Leader University Associate Professor, University of CambridgDavid Bulmer studied pharmacology at the University of Manchester, and obtained his PhD in physiology (central processing of sensory input from the heart) with Prof Mike Spyer at University College London. Following post-doctoral training with Prof David Grundy on sensory function in the gastrointestinal tract at the University of Sheffield, David joined the Neuroscience & Gastrointestinal Centre of Excellence in Drug Discovery (CEDD) at GlaxoSmithKline as an electrophysiologist in the visceral pain group, progressing to lead a translational research group within the Immuno-Inflammation CEDD. David left GSK in 2009, joining Queen Mary University of London (QMUL) on a Medical Research Council funded Skills Gap Award as a lecturer in Neurogastroenterology. At QMUL, David established a word class translational neuroscience group based on the use of human tissue to study the mechanisms of sensory signalling from gut in health and disease. A notable achievement of his group have been the development of “first in man” recordings and subsequent detailed characterisation of human visceral nociceptors. In July 2017, David joined the Department of Pharmacology, University of Cambridge, where he has quickly established a translational human tissue lab. | Eddy Stevens PhDCSO, Metrion BiosciencesDr Edward Stevens has over 20 years’ experience in ion channel drug discovery. Before joining Metrion, Eddy held the position of Chief Scientific Officer at Ario Pharma, co-ordinating Ario’s TRPA1 lead discovery project in collaboration with a global pharmaceutical company. Prior to this, Eddy spent 8 years at Pfizer, initially at Sandwich where he held the position of Head of Ion Channel Electrophysiology. Eddy then moved to Pfizer Neusentis in Cambridge where he took up the same role. This included leading pharmacology support for all Neusentis ion channel programmes and included the management of a potassium channel programme which successfully progressed to lead development stage. Prior to his role at Pfizer, Eddy was previously Chief Operating Officer of NeuroSolutions and Section Head at BioFocus (Charles River). He completed post-docs at the University of Cambridge and Parke-Davis UK. |