Identification of druggable targets for C9orf72-related toxicity via an innovative CRISPR/Cas9 kinome-wide screen

PI Dr Arpan Mehta
Co-investigators Dr Wenting Guo
Collaborators Prof. Kevin Talbot and Prof. Colin Smith
PI organisation University of Dundee
Funding awarded £356,937
Completion date 1st October 2025 (18 months)

This study aims to identify a class of proteins called “kinases” that may act as pivotal cellular switches in the ALS/MND disease process. There’re currently >100 approved drugs that target kinases; yet, in ALS, there’s been little dedicated research on kinases, meaning that there’s an urgent unmet need. By studying the commonest genetic cause of ALS/MND—a fault in the C9ORF72 gene—we’ll harness state-of-the-art human stem cell and gene-editing technologies to screen for novel druggable targets. We’ll examine for kinases that modulate motor neuron death when harmed with excessive glutamate neurotransmitter and toxicity imparted by immune cells (mimicking the toxicity seen in real life). We’ll then validate the top kinase potential targets by multiple methods, including via human postmortem tissue. Ultimately, this groundbreaking foundational work will set the scene for the next stage of discovery using the results generated, aiming to uncover druggable targets that prevent MN death.