How CRISPR Transforms Modern Drug Discovery

While the transition away from in vitro and immortalized cell assay systems has been underway over the last decade, the pace increased with the advent of easily manipulated stem cells to create fit-for-purpose biochemical and high content, high throughput screens. The principal accelerator here has been CRISPR editing to provide organotypic and disease specific models, including direct application of patient-sourced cells and assembled organoids (disease and control) as platforms for drug SAR and efficacy testing.

As Andrew Bassett  from the Wellcome puts the matter: "such cells can be generated in sufficient numbers to be able to perform whole genome genetic screens to identify molecular and cellular mechanisms of disease and therapeutic targets, and also for high throughput drug screening to identify compounds that may be able to revert the disease phenotype. Differences between patient-derived and control cells can be used to identify potential therapeutic targets or agents." (Ref. 1). A compelling example in an underserved area of research lies in the development of CRISPR driven new assays for glioblastoma (Ref. 2).

Diving deeper reveals how powerful CRISPR manipulation can be in effectively affording knock-in, through activation (CRISPRa), or knock-out, through interference (CRISPRi), of traits/phenotypes subject to targeting and modulation by candidate drugs (Refs. 3-5 and graphic below taken from Ref. 4). The technology is also extensible to organoids, deriving further informational value from this more physiologically meaningful cell platform (Refs. 6,7).