SfN Poster – Pharmacological validation of a human, pain-relevant high throughput assay
Date: Nov 15, 2017
Presentation Time: 4:00 pm – 5:00 pm
Presentation Number: 767.28
Poster Board Number: AA12
Progress in developing higher throughput assays for peripheral pain has largely been limited by the lack of disease-relevant human neuronal cultures. However, with the advent of the human induced pluripotent stem cell (hiPSC) technology, human sensory-like neurons can now be produced in sufficient volumes to enable plate based screening.
We have developed a high throughput screening assay where hiPSC-derived sensory neurons (see abstract by Karila et al. 2017 for hiPSC neuronal culture characterization) are used in combination with the Cellaxess® Elektra electric field stimulation (EFS) technology to produce an assay which is well-suited to investigate compound effects on neuronal excitability.
The physiological relevance to human pain conditions, such as neuropathic pain, was demonstrated by activity of clinical and tool compounds representing a wide range of mechanisms for chronic pain for example NaV1.7 subtype specific ligands; mexiletine, gabapentin and naproxen. The results were compared to both rodent and human data and we found good agreement between inhibition of excitability as measured by EFS in human iPSC-derived sensory neurons and effect in lower throughput conventional models such as human dorsal root ganglion (DRG) electrophysiology.
The simultaneous EFS and imaging of the entire plate enables identification of test compounds that modulate the neuronal excitability in a high capacity fashion while delivering electrophysiology-like accuracy as demonstrated by the pharmacological characterization of both clinically used drugs and novel subtype-specific sodium channel inhibitors. The results strongly suggest that the Cellaxess Elektra platform provides a dramatically higher-throughput means of quantifying the excitability of human iPSC-derived sensory neurons. This enables identification and prioritization of molecules that are likely to also modulate the excitability of native tissue earlier on in the drug development process.
Authors: M. KARLSSON, S. LARDELL, C. NODIN, A. KARLSSON, J. PIHL, P. KARILA;
Cellectricon AB, Mölndal, Sweden