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Development of TRPML1-4A assays across manual, automated patch-clamp, and fluorescence-based platforms

The development and validation of electrophysiological assays to study TRPML1 is important to understand the function and pharmacology of the channel. We used a TRPML1 variant that lacks the endo-lysosomal retention sequences (TRPML1-4A), enabling the channel to express at the plasma membrane3. As such channel behaviour can be characterised by means of whole-cell patch-clamp and fluorescence-based techniques.

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GLP hERG testing assay validation following ICH E14/S7B 2022 Q&A best practice guidelines

The ICH E14/S7B 2022 Q&As stipulate that in vitro hERG assessments should be conducted in accordance with Good Laboratory Practice (GLP). We present a GLP compliant study using the conventional manual patch-clamp technique in accordance with the ICH E14/S7B Q&A best practice guidelines to establish in-house IC50 values for ondansetron, moxifloxacin and dofetilide.

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Multi-assay high-throughput drug repurposing screen: KCNC1 case study

Eliana is a two-year-old from Canada with a de novo mutation (V434L) in her KCNC1 gene which encodes for the Kv3.1 channel in central nervous system neurons such as cerebellar neurons and GABAergic interneurons. The mutation manifests as a variety of neurological disorders which can include myoclonic epilepsy and ataxia due to K+ channel mutation, developmental epileptic encephalopathy (DEE), or hypotonia, depending on the specific variant. Although Eliana does not exhibit typical DEE, she suffers from hypotonia, cortical-visual impairment, vertical nystagmus, and global delays.

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Endo-lysosomal patch clamp assay

The endo-lysosomal system is a series of intracellular organelles responsible for recycling and degradation of macromolecules. Endo-lysosomes express several functionally diverse ion channels, crucial for regulating organelle trafficking and intracellular signalling as well as maintaining the acidic luminal pH for optimal enzymatic activity. Dysfunctions within the endo-lysosomal system are associated with multiple disorders including lysosomal storage disorders and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Lysosomal ion channels have therefore gained significant attention as potential targets for novel therapeutics.

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Identification of novel ion channel binders: TRPA1 antagonist case study

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.

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The Nav1.5 late current in WT and Nav1.5-ΔKPQ mutant channels: an automated patch clamp LQT3 electrophysiological assay comparison

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.

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Drug discovery collaboration between Japanese pharma and a UK SME CRO successfully developed novel small molecule inhibitors of the Kv1.3 channel to treat autoimmune disease

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. 

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Development of an impedance-based screening assay for cardiac safety and cardiotoxicity detection in stem cell-derived cardiomyocytes

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).

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Investigating the correlation between thallium flux and automated patch-clamp for ion channel activators

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. However, these assays are a surrogate for channel function and it is important to have an appropriate panel of orthogonal and translational electrophysiology assays in place to confirm activity at the channel of interest.

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Using new in vitro cardiac ion channel assays and in silico models to predict proarrhythmic risk with automated patch clamp data

The FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is designed to remove the over-reliance on hERG data to predict human clinical cardiac risk⁽¹⁾, with recent results suggesting that inclusion of additional cardiac ion channels and assays (e.g. peak and late Nav1.5, Cav1.2, dynamic hERG⁽²⁾) improve risk predictions of in silico action potential models⁽¹⁾. The CiPA working groups currently use a mixture of manual and automated patch clamp (APC) platform data, but future CiPA drug screening will likely rely on APC data.

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