Drug Discovery


engineered animals has prevented their routine use in the preclinical studies.


RNA interference (RNAi) in tandem with CRISPR/Cas9 technology provides a solution to this problem. With the evolution of RNAi and the advent of CRISPR/Cas9 technologies, the speed and precision in which genetically-engineered mouse models can be created is unprecedented. Powerful new algorithms and expression vectors give us the ability to generate reliable RNAi tools, which can be exploited experimentally to effective- ly and reversibly silence nearly any gene or gene combinations, not only in vitro but also in live mice and soon rats and higher organisms. In addi- tion, continued progress in the implementation of CRISPR/Cas9 as a gene editing tool allows us to introduce specific genetic alterations in animals and create ‘designer’ models. Synergising these technologies will help us to better model clinical disorders and evaluate genetic and environmental stimuli in animal models, which will increase our confidence in predicting drug responses in humans and push drug discovery research into a new era. In short, RNAi and CRISPR/Cas9 will bring us into a whole new era of preclinical in vivo valida- tion, where thorough investigation of mechanisms are not only possible but will become a prerequi- site for entry into the clinical arena.


The genomic revolution


Neither RNAi nor CRISPR/Cas9 would have much meaning today were it not for a massive effort that began in 1990 to identify and map our genes. The


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RNAi: A game-changing tool RNAi is a naturally-occurring process that regu- lates gene expression in many organisms and can


Drug Discovery World Fall 2017


completion of the Human Genome Project (www.genome.gov) in 20036,7, among other things, gave us many new drug targets to explore, and functional genomics tools have endeavoured to prioritise these targets and translate that knowl- edge into rational and reliable drug discovery8. The minefield is huge. Scientists from the Human Genome Sequencing Commission estimated in 2004 that there are between 20,000 and 24,000 protein coding genes9. This means we have 10s of 1,000s of genes and at least as many proteins as potential tar- gets for drug intervention to control human disease or injury, light years from the 600 or so proteins that drugs have targeted over the past 100 years2. But although human genomics has the capacity to dramatically increase the number of potential drug targets, the limited knowledge available about these targets has also led to an increased attrition rate for early-stage research projects8. So, we need technologies capable of identifying, vali- dating and prioritising thousands of genes to select the most promising targets.


It goes without saying that these technologies need to be high throughput to develop depth of knowledge about each target. And we need inte- gration of multiple technological platforms to understand the role of genes in biological pathways that are involved in various diseases to select best points of intervention.


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