High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models
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, phenotyp...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/92491 |
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| author | Thomas J O'Brien Ida L Barlow Luigi Feriani André EX Brown |
| author_facet | Thomas J O'Brien Ida L Barlow Luigi Feriani André EX Brown |
| author_sort | Thomas J O'Brien |
| collection | DOAJ |
| description | 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 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 suggest that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases. |
| format | Article |
| id | doaj-art-a9d82fa71b3b4b1198c2a9fc4512d5a1 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-a9d82fa71b3b4b1198c2a9fc4512d5a12025-01-08T13:43:02ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011210.7554/eLife.92491High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease modelsThomas J O'Brien0Ida L Barlow1Luigi Feriani2André EX Brown3https://orcid.org/0000-0002-1324-8764Institute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United KingdomInstitute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United KingdomInstitute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United KingdomInstitute of Clinical Sciences, Imperial College London, London, United Kingdom; MRC London Institute of Medical Sciences, London, United KingdomThere 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 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 suggest that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.https://elifesciences.org/articles/92491computational ethologyDrug repurposingdisease models |
| spellingShingle | Thomas J O'Brien Ida L Barlow Luigi Feriani André EX Brown High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models eLife computational ethology Drug repurposing disease models |
| title | High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models |
| title_full | High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models |
| title_fullStr | High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models |
| title_full_unstemmed | High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models |
| title_short | High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models |
| title_sort | high throughput tracking enables systematic phenotyping and drug repurposing in c elegans disease models |
| topic | computational ethology Drug repurposing disease models |
| url | https://elifesciences.org/articles/92491 |
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