High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models

Area of Science:

• Genetics
• Neuroscience
• Drug Discovery

Background:

• Thousands of Mendelian diseases lack approved treatments, necessitating scalable and cost-effective drug development strategies.
• Phenotypic screening in model organisms offers a viable approach for identifying therapeutic candidates when drug targets are unknown.
• Developing effective assays for complex, pleiotropic disorders like neuromuscular diseases can be challenging.

Purpose of the Study:

• To establish a high-throughput imaging and quantitative phenotyping platform for systematically evaluating C. elegans models of human Mendelian diseases.
• To demonstrate the utility of a standardized assay for diverse disease models and facilitate drug repurposing.
• To assess the scalability and cost-effectiveness of this approach for addressing the large number of Mendelian diseases.

Main Methods:

• Utilized CRISPR genome editing to generate 25 C. elegans models of human Mendelian diseases.
• Employed a single, standardized high-throughput imaging assay to quantify multiple phenotypic features across all disease models.
• Performed a drug repurposing screen using an FDA-approved compound library on selected C. elegans disease models.

Main Results:

• All but two C. elegans strains exhibited significant phenotypic differences compared to wild-type controls.
• Diverse phenotypes were observed, with genes of predicted related functions often causing similar behavioral alterations.
• Identified two FDA-approved compounds that rescued the behavioral phenotype in a model of UNC-80 deficiency.

Conclusions:

• A single, multi-phenotypic assay can be systematically applied to a diverse range of Mendelian disease models in C. elegans.
• High-throughput worm tracking offers a scalable, rapid, and cost-effective method for drug repurposing, suitable for the vast number of Mendelian diseases.
• This platform accelerates the identification of potential treatments for rare genetic disorders.