With almost unlimited genome engineering opportunities, CRISPR holds great promise for transforming drug discovery and development

The power of the CRISPR technology lies in its unprecedented ease and control when editing the genome. When you think of the drug development pipeline there are multiple steps that can benefit from this emerging technology.

In early discovery, CRISPR screens can reveal new drug targets and cell-based models can be engineered to mimic disease to increase translatability when searching for new compounds and going down the path of lead optimization and delivery of a candidate compound. But it does not stop here. Further preclinical development can be enhanced by CRISPR by applying the technology in in vivo target validation or generating new in vivo disease models with improved clinical relevance. Moreover, developments are ongoing at various CRISPR biotech companies to provide CRISPR-based gene therapy solutions for genetic diseases. The simplicity of the system, the accessibility to researchers, and the relatively quick way of genome engineering hold real promise for accelerating drug development and reducing attrition rates of compounds.

[Tune into this webinar on the utilization of CRISPR/Cas9 technology in drug discovery.]

There is still a whole field out there to explore in using CRISPR screens for discovery of new disease targets. So far most of the publications are describing pooled screening in the oncology field. Pooled screening requires relatively clear-cut readouts, such as cell proliferation, cell death or sortable marker proteins. However, in other disease areas often more complex functional readouts are needed for a meaningful outcome of the screen. Arrayed screening allows for phenotypic readouts that are usually not amenable to a pooled approach, including high content analysis. Arrayed CRISPR libraries are now emerging with the guide RNA being either expressed from lentivirus or produced as a synthetic molecule. CRISPR faces the same challenges as RNA interference, where delivery is key to efficient screening. Using CRISPR screens in drug development is foreseen to grow now that CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens are coming into play, with the latter one giving the advantage of screening for gain-of-function.

In target validation the CRISPR technology has the advantage over RNAi to fully abolish gene expression as opposed to the transient and incomplete silencing of the target as achieved by siRNAs. This also has a profound impact on rescuing the phenotype to confirm target specificity by adding back methodology, which will give far better interpretable results in case of a complete knockout by CRISPR as opposed to an incomplete silencing by RNAi. Therefore, it is most likely that CRISPR-mediated knock-outs and knock-ins will be replacing the current target validation methods in the near future. Delivery systems such as viruses even allow for CRISPR-mediated target validation in a broad spectrum of primary cells that are usually more difficult to edit using conventional transfection systems.

The relative ease of engineering with CRISPR will certainly contribute to the development of more complex cellular assays with improved predictability for drug therapies. Also promising is the stem cell technology maturing in parallel with the CRISPR field. Genetic disorders can be mimicked by introducing genetic defects in stem cells, which can be subsequently differentiated into disease-relevant cell types.

Who would have thought 10 years ago that a revolutionizing technology such as CRISPR would re-shape the landscape of biomedical research? Yet this is the fortunate position we are currently in as researchers. It is an exciting time to be working in this rapidly expanding field and the future will tell us if the CRISPR promise in drug discovery can be fulfilled.