Systematic creation and phenotyping of Mendelian disease models inC. elegans: towards large-scale drug repurposing

Abstract There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that are relatively inexpensive compared to traditional drug development. In the absence of a validated drug target, phenotypic screening in model organisms provides a route for identifying candidate treatments. Success requires a screenable phenotype, however the right phenotype and assay may not be obvious for pleiotropic neuromuscular disorders. Here we show that high-throughput imaging and quantitative phenotyping can be conducted systematically on a panel of C. elegans disease model strains. We used CRISPR genome-editing to create 25 worm models of human Mendelian diseases and phenotyped them using a single standardised assay. All but two strains were significantly different from wild type controls in at least one feature. The observed phenotypes were diverse, but mutations of genes predicted to have related functions in their human orthologs led to similar behavioural differences in worms. As a proof-of-concept, we performed a drug repurposing screen of an FDA approved compound library, and identified two compounds that rescued the behavioural phenotype of a model of UNC80 deficiency. Our results show that a single assay to measure multiple phenotypes can be applied systematically to diverse Mendelian disease models. The relatively short time and low cost associated with creating and phenotyping multiple strains suggests that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.