(1346-C) Modeling rare genetic diseases for drug discovery with C. elegans quantitative high throughput screening (qHTS)
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: Model organisms have been used extensively in basic research to study the biological pathways associated with human physiology and disease. In drug discovery research these systems play a critical role from high-throughput screening (HTS) to assessing the effects of lead compounds in more physiological and phenotypically relevant settings. Previous studies have demonstrated the feasibility of quantitative high-throughput screening (qHTS) across single cell organisms including S. pombe yeast, bacteria, and P. falciparum in cellular co-culture, however, the use of multicellular systems has been limited by the technical requirements associated with HTS. Here we developed a platform for qHTS with the multicellular organism Caenorhabditis elegans that can serve as not only a surrogate for infectious nematodes, but also as a model for complex human genetic disorders. C. elegans offers many advantages as a qHTS compatible model organism including its short life span, small size, and ease of genetic tractability. This paradigm was employed across a 384-well microtiter plate compatible viability qHTS using laser-scanning cytometry of GFP-expressing worms to investigate phenotype-modifying structure-activity relationships (SAR) of a focused drug library. Active chemotypes were further investigated with several follow-up studies, including life-stage progression and Omics studies. Broader applications of this platform will include using C. elegans as a phenolog for human pathologies, including current work with a humanized worm model expressing Parkinson’s Disease-causing mutations and in the study of TANGO2 deficiency in worms employing a genetic knockout of the nematode gene homolog.