Targeting neuronal excitability in MND for high-throughput drug screening

Disturbances in neuronal function (excitability) are considered a hallmark of MND. Abnormalities known to occur early and are considered to precipitate neuronal degeneration and generate symptoms of the disease. Excitability changes therefore represent a key therapeutic target.

In vivo human neurophysiology and in vitro electrophysiology provide detailed insights into disturbances in neuronal function. While related, these two strands of MND research - in vivo and in vitro neurophysiology - have not previously been aligned. This project will join clinical neurophysiology and laboratory electrophysiology together, generating a unique platform for pharmacological screening and understanding disease pathophysiology.

Leveraging our expertise in clinical neurophysiology and our track record with MND induced pluripotent stem cell (iPSC)-derived neurons, we will develop a novel high-throughput pharmacological screening assay using cutting-edge multi-electrode array electrophysiology. This will substantially accelerate drug discovery targeting electrical impairments.

Whilst neuronal excitability is disturbed in MND, many patients present with heterogeneous profiles, which must be considered by therapeutic approaches. For the first time, we will generate iPSCs from MND patients with clinically-defined electrophysiological characteristics, identified through detailed testing of both central and peripheral nervous system excitability. Using our new high-throughput approach, we will link our laboratory and clinic work to establish drug screening assays on electrophysiologically stratified patient iPSC-derived neurons.

As a result, the study will establish a unique platform for testing novel therapeutic agents in order to rescue neuronal function disturbances specific to individual patients. Furthermore, we will make electrophysiological stratified iPSCs available to the MND research community.