Quinolinones as a Novel Therapeutic Strategy in ALS

Background ALS is a fatal and severely debilitating neurodegenerative disorder that overlaps with FTD. There are few treatments with meaningful efficacy, highlighting the urgent need to develop novel therapeutic strategies. This
project investigates the effectiveness of quinolinone analogues as a novel and highly innovative therapeutic strategy.
We have previously demonstrated that these compounds display broad efficacy against key disease-relevant phenotypes in a range of cellular and zebrafish models. These compounds prevent mis-localisation of TDP-43 and FUS to the cytoplasm, formation of mutant SOD1, TDP-43 and FUS inclusions, as well as ER stress and apoptosis in neuronal cell lines expressing mutant TDP-43, SOD1 or FUS. They also improve motor performance in zebrafish expressing mutant CCNF (encoding cyclin F). Hence these compounds display efficacy in multiple cellular disease models, against four different proteins that misfold in ALS, as well as motor impairment in vivo. This provides evidence that these compounds will be broadly effective in several different forms of ALS.