Mapping Genetic Interactions: A Path to Discover Efficacious Drug Targets

Challenge: One of the major challenges for disease treatment is the identification of efficacious drug targets. To overcome the problem, one proposed solution is the use of combined drug therapy that either targets two genes simultaneously or interfere with a single gene with loss-of-function of another one. In both cases this will induce cell synthetic lethality. A synthetic lethal screen has been successfully used in yeast to map genetic networks and was instrumental in predicting functions of thousands of poorly characterized genes. However, to date, no such system enabling quick screening for novel synthetic lethal genes or combined drug targets has been developed in human cells.

Solution: To perform such human single cell synthetic lethality screen, the team developed the new CIGI technology (CRISPR-induced genetic interaction). CIGI could identify new drug targets and biomarkers by comprehensively mapping interactions between established disease pathways and all known genes. CIGI could also pinpoint specific effects to genetic background in diverse environments such as in systems that model disease progression or in patient-specific cells. The team made its proof of concept by focusing on the Hippo signaling pathway which controls organ size in animal development.

Achievements/Impact: Using CIGI, the team performed a genome-wide synthetic lethal screen and mapped the elements of the genetic network interacting with the Hippo signaling pathway components. The researchers also identified many novel synthetic lethal genes or combined drug targets. Queen’s University is exploring how to protect the technology (patent). Based on these results, there is already a CQDM pharma member that has exercised its option to use this technology.