We are delighted to present the second speaker in our webinar series – Professor Stephen Tucker from the Department of Physics at the University of Oxford. Stephen speaking on the topic of the TASK-1 K2P channel and his talk will be entitled “Defective X-gating caused by de novo mutations in the TASK-1 K2P channel (KCNK3) underlies a developmental disorder with sleep apnea”.

The webinar took place on Thursday 16th September 2021 at 16:00 BST.

One aim of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is to improve drug safety testing in pre-clinical development by evaluating the proarrhythmic risk of a compound. Validation studies confirm that testing the effect of compounds on an increased number of human cardiac ion channel currents including INa (NaV1.5 peak and late current) as well as IKr (hERG) leads to improved prediction of their clinical risk.

To meet the FDA’s CiPA requirements for improved in silico action potential modelling and arrhythmia prediction, we have successfully created and implemented the challenging Milnes hERG cardiac safety assay

Rapidly activating and desensitising ligand-gated ion channel receptors can provide a technical challenge on automated patch clamp electrophysiology platforms. This can affect their biophysics, pharmacology and assay reliability. We present data on an optimised and validated acid-activated receptor assay on the QPatch that is stable enough for drug discovery screening.

As an alternative to standard pharmacological procedures for NaV1.5(Late) assays, we present a more reliable and accurate NaV1.5(Late) assay on QPatch that removes the requirement for activators like veratridine and ATX-II and delivers improved cardiac safety screening reliability and cost.

There is growing interest in automated patch-clamp (APC) assays for ligand-gated targets which are expressed throughout the peripheral and central nervous system. The Acid-Sensing Ion Channel (ASIC) family comprises combinations of ASIC1-4 proteins that form acid-activated cation-selective channels.

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.

The cardiac late Na+ current (late INa) generates persistent inward currents throughout the plateau phase of the ventricular action potential and is an important determinant of repolarisation rate, EADs and arrythmia risk¹. As inhibition of late INa can offset drug effects on hERG and other repolarising K⁺conductances, it is one of the key cardiac channels in the Comprehensive in vitro Pro-arrythmia Assay (CiPA) panel being developed by the FDA to improve human clinical arrythmia risk assessment²̛ ³.

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 specialist target class knowledge and screening technology such as automated patch clamp (APC) electrophysiology.

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⁽¹⁾. 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. Therefore, new assays are required to characterise chronic structural and functional effects in human cells earlier in drug discovery. Impedance-based technology can provide more accurate chronic cardiotoxicity measurements in an efficient manner using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).