Genomics


How high-throughput CRISPR is set to deliver knockout performance in drug discovery


CRISPR-Cas9 has rapidly transformed our ability to perform targeted gene editing. While the technique has received much interest for its potential in the field of gene therapy, advances in its high-throughput use mean it can now open up a wealth of opportunities in drug discovery too.


C


RISPR-Cas9, short for clustered regularly- interspaced short palindromic repeats and CRISPR-associated protein-9, has quickly


established itself as an important tool for precision gene editing. This powerful technology has trans- formed our ability to precisely target genomic sites, proving to be faster, cheaper and more accurate than other existing genome editing methods. While other gene editing technologies such as


zinc finger nucleases (ZFNs) and transcription acti- vator-like effector nucleases (TALENs) have played a key role in expanding our gene editing capabili- ties, these approaches have their limitations. Unlike ZFN and TALEN approaches, CRISPR- Cas9 uses short synthetic guide RNAs (gRNAs) that direct the Cas9 endonuclease to act on specific genomic sites. As this specificity results from the gRNA, changing the target requires a relatively simple tweak to the RNA sequence. This simplicity enables gene editing to be direct-


ed towards essentially any site faster and more cost-effectively than other techniques1. Coupled with the fact that the latest generation of platforms offer significantly higher editing efficiency,


Drug Discovery World Spring 2018


CRISPR-Cas9 is now seen by many as the pre- ferred gene editing approach for a wide variety of biotech applications2. The editing efficiency and simplicity of the


CRISPR-Cas9 system has unlocked a wealth of gene editing potential in biotechnology and medicine. To date, much of the interest towards CRISPR-Cas9 has been on its potential for human gene therapy and developing more disease-resistant crops. However, recent advances in high-through- put platforms, such as arrayed screening libraries, mean CRISPR-Cas9 is now emerging as a key tool for drug discovery, from target identification and validation through to the development of more translational preclinical models3.


High-throughput gene editing for target discovery Currently, one of the biggest challenges in drug dis- covery is the search for novel, validated and drug- gable targets. Genome-wide loss-of-function screen- ing is a well-established and powerful approach for the discovery of genes and pathways associated with biological processes. While the previous generation


61


By Dr Paul Avery and Dr Richard Massey


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72