Ion channels play a key role in regulating resting membrane potential and cell excitability and are attractive targets for therapeutic intervention.
Thallium (Tl+) flux assays, which measure the flow of Tl+ through potassium channels, offer a high throughput method for the identification of potassium channel activators.
Recent work by FDA and HESI CiPA working groups indicate that in vitro hERG, Nav1.5 and Cav1.2 potency data in addition to dynamic hERG kinetic data is required to accurately predict proarrhythmic risk.
Cardiac toxicity remains the leading cause of new drug safety side-effects. Current preclinical cardiac safety assays rely on in vitro cell-based ion channel assays and ex vivo and in vivo animal models. These assays provide an indication of acute risk but they do not always predict the effect of chronic compound exposure, as recently seen with oncology drugs.
Metrion Biosciences is a UK based CRO, located at Granta Park in Cambridge. Our team has substantial expertise in providing research services to deliver preclinical and clinical stage drug candidates, and has a proven track record of providing high quality drug discovery services to our customers for ion channel targets on a fee-for-service or collaboration basis. The Metrion team takes pride in providing a knowledgeable, collaborative and flexible service to all customers, whether for small stand alone projects or fully integrated drug discovery programmes.
Ion channels represent 15 – 20% of historic drug approvals and recent drug discovery projects. Many ion channel families (Nav, Cav, TRPx and GABA) are validated as therapeutic targets based on human genetics, animal models and selective pharmacology. However, ion channels are challenging targets requiring expert target class knowledge and specialised screening technology such as automated patch-clamp (APC) electrophysiology.
Domainex and Metrion Biosciences have formed an alliance to identify new chemical hits against ion-channel targets. Key to this collaboration are Domainex’s experience in hit identification and Metrion Bioscience’s expertise in ion channel screening and pharmacology.
Presentation from Metrion Biosciences’ external speaker series, Professor Nikita Gamper, University of Leeds, 5th February 2019.
Activated effector memory T-cells (TEM) have been implicated in the pathogenesis of autoimmune diseases.1 Activated TEM cells express high levels of the voltage-gated potassium channel Kv1.3, which functions to control cell excitability.
Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are a promising tool for assessment of drug-induced arrhythmias during non-clinical drug development. This technology is under evaluation by the FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative and the Japanese iPS Cardiac Safety Assessment consortium (JiCSA) to develop new cardiac safety assessment measures to refine current S7B and E14 guidelines.
New cardiac safety testing guidelines are being finalised, as part of the FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, which aim to remove the over-reliance on screening against the hERG channel by expanding the panel to include hNav1.5, hCav1.2, hKv4.3/KChiP2.2, hKir2.1 and hKv7.1/KCNE1 human cardiac ion channels.