Applications of CRISPR genome editing technology in drug target identification and validation

ABSTRACT

Introduction: The analysis of pharmaceutical industry data indicates that the major reason for drug candidates failing in late stage clinical development is lack of efficacy, with a high proportion of these due to erroneous hypotheses about target to disease linkage. More than ever, there is a requirement to better understand potential new drug targets and their role in disease biology in order to reduce attrition in drug development. Genome editing technology enables precise modification of individual protein coding genes, as well as noncoding regulatory sequences, enabling the elucidation of functional effects in human disease relevant cellular systems.

Areas covered: This article outlines applications of CRISPR genome editing technology in target identification and target validation studies.

Expert opinion: Applications of CRISPR technology in target validation studies are in evidence and gaining momentum. Whilst technical challenges remain, we are on the cusp of CRISPR being applied in complex cell systems such as iPS derived differentiated cells and stem cell derived organoids. In the meantime, our experience to date suggests that precise genome editing of putative targets in primary cell systems is possible, offering more human disease relevant systems than conventional cell lines.

KEYWORDS:

• CRISPR
• drug discovery
• genome editing
• target validation

Article highlights

• CRISPR technology is proving a powerful tool for target validation studies.

• The technology is beginning to be applied in linking non-coding genetic association signals to their targets.

• Genome editing of primary cells may provide a human disease relevant system better able to translate findings to the clinic.

• Unbiased genome-wide CRISPR screens can identify novel drug targets.

• CRISPR technology has been developed to edit genes in a variety of model organisms.

This box summarizes key points contained in the article.

Acknowledgments

We thank members of the GSK Genome Editing Special Interest Group for helpful discussions. Due to a large body of relevant publications in the field, only selected references are cited.

Declaration of interest

Q Lu, GP Livi, S Modha, R Macarron and DJ Dow are all employees of GlaxoSmithKline.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

K Yusa is supported by the Wellcome Trust. All other authors are supported by GlaxoSmithKline.