Chapter 8 - Second Generation Genome Editing Technologies in Drug Discovery

Abstract

The advent of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (CRISPR-Cas) era has ushered in a significant paradigm shift of the accepted approaches to drug design and discovery and a technological revolution for applications requiring efficient gene editing. Previous approaches focussed on modulating validated upstream targets using methodologies involving the activation/inactivation of genetic regulatory elements. These strategies accomplish the outcomes with small molecules, antibodies, enzymes (biologics), interfering RNA (miRNA, shRNA, RNAi), stem cell therapy (embryonic, mesenchymal, haematopoietic, etc.), and traditional, generation zero gene editors, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). This chapter is focussed on the next generation of CRISPR-Cas editors, their applications and the relationship of these new techniques with the future of drug discovery and its business landscape. These new Cas nucleases: (1) are versatile; (2) can be efficiently and economically modified to affect target specificity and recognition properties; (3) are efficiently delivered and expressed in targeted cells; and (4) are cost-effective when compared to increasingly outdated methodologies utilising embryonic stem (ES) cells, ZFNs and TALENs. Using the CRISPR-Cas gene editors as nuclease-dependent modification tools will address several of the technical challenges that arise with traditional nucleases.