12.08.2024
Channelopathy profiling
In his second preclinical ion channel drug discovery blog, Marc Rogers gives a comprehensive review of how the explosion in patient genetic screening and need to profile the thousands of novel channelopathy mutations is being met by the ability of high throughput automated patch clamp to rapidly characterise their biophysical and pharmacological properties, and thereby reliably inform clinical treatments.
After academic research as a neuroscientist and 20 years of commercial ion channel drug discovery, Marc Rogers now works as a freelance blogger, advisor and consultant for clients in the UK, EU and US where he shares his expertise and enthusiasm for all aspects of ion channel screening. He is particularly interested in automated patch clamp, and exploiting the potential of human iPS stem cell assays to facilitate the successful translation of new drugs into the clinic.
The rapid expansion in patient genetic screening for common, rare and undiagnosed diseases has revealed a growing number of mutations in specific genes, but their significance for clinical diagnosis and understanding of disease severity and progression are frequently unknown. Disease-related mutations in ion channels are called channelopathies and they are typically characterised using cell-based and patch clamp assays to assess their effects on protein trafficking, cell surface expression and overall activity, and to profile subtle changes in biophysical properties and pharmacology. There are now over 1,300 human syndromes linked to channelopathies, and for some common diseases like epilepsy each ion channel may harbour hundreds or thousands of unique mutations, many of which have an unknown effect on channel function. The challenge to profile the growing number of channelopathies is now being met by high throughput automated patch clamp assays which can rapidly and reliably assess their properties and help to determine the clinical and disease risk of each mutation. This article will highlight recent case studies of channelopathy profiling by APC for cardiac and neuronal voltage-gated Nav1.5, Nav1.2, Nav1.6, Nav1.7, hERG, Kv7.x, Kv3.x, K2P, Cav1.x and Cav3.3 channels and NMDA GluR ligand-gated ionotropic receptors, and compare this technique to other methods for variant characterisation such as evolutionary analysis and in silico protein homology (e.g. AlphaMissense, RoseTTaFold) and atomistic models. Finally, translational case studies and assays will be presented that can help to confirm and extend the biophysical predictions of channelopathy effects into native and human cells.
