Complex human diseases such as cancer can arise from defects in multiple molecular pathways. Despite the need for new combination therapies that simultaneously target multiple disrupted gene networks, previous techniques for discovering disease-related gene combinations have been expensive, labor-intensive, and challenging to scale.
Researchers developed a simple, efficient screening platform to identify gene pairs that act synergistically to regulate disease-related cellular processes. The authors used a recently developed approach called combinatorial genetics en masse (CombiGEM) to rapidly create a library of 23,409 pairwise combinations of guide-RNAs (gRNAs).
The gRNA molecules form a complex with the Cas9 enzyme to generate mutations at specific genomic sites. Leveraging this genome-editing approach, known as the CRISPR-Cas9 system, the authors delivered gRNA pairs into human ovarian cancer cells, thereby simultaneously generating mutations in gene pairs.
The CombiGEM-CRISPR screening platform revealed several gene pairs that acted synergistically to regulate cancer cell growth. For example, gRNA pairs that simultaneously targeted the KDM4C and BRD4 genes reduced cancer cell growth to a greater extent than individual gRNAs that targeted only one of these genes.
According to the authors, the CombiGEM-CRISPR platform could facilitate the discovery of synergistic drug combinations for complex human diseases.
http://www.pnas.org/content/early/2016/02/09/1517883113
Screening platform for drug discovery
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