Genome Editing in Drug Discovery

CRISPR is widely applied to create cellular and animal models of disease, both for the identification of new drug targets and for understanding the efficacy of new drug candidates within a discovery program (Lundin et al. 2020). CRISPR is used to create specific mutations in genes to understand the effect of that mutation on gene function and to introduce molecular tags into genes to track gene expression. The latter approach has been widely adapted to characterize the efficacy of Proteolysis Targeting Chimeras (PROTACs) drugs. PROTACs are a recently discovered class of small‐molecule drugs that rather than inhibiting the function of a drug target, act to degrade the target protein. To understand the efficacy of PROTAC drugs in cellular models of disease, the drug target is typically tagged with a short protein sequence that enables the creation of assays that allow PROTAC‐mediated degradation of the target to be followed in real time in an immortalized cell line or animal model of disease. CRISPR has revolutionized the ability to generate transgenic animal models of disease, both reducing the timelines and number of animals required for the creation of an animal model through the ability to highly efficiently edit the genome of the single cell embryo, while again enabling the creation of complex models of disease not previously possible.

CRISPR is being widely applied in the field of CAR‐T cell therapy both to enable precise insertion of the CAR, but also to identify and delete other T‐cell genes to enable improved efficacy of the cell product (Liu et al. 2017). There is also huge interest in the potential of CRISPR as a medicine in its own right to correct gene mutations in rare and perhaps common diseases and a number of biotechnology companies have been established to bring CRISPR medicines to the clinic, including Editas, CRISPR Therapeutics, Beam Therapeutics, Verve Therapeutics and Intellia. The first clinical studies of medicines to treat β‐thalassemia and Sickle Cell Disease started in 2019 with highly promising results in the first patients, with the first in‐vivo gene editing clinical trials in diseases such as Transthyretin amylodosis in which CRISPR is being used to delete genes in the patient liver, due to start in 2022. Many further projects are in discovery to develop treatments for a range of diseases including α1‐antitrypsin deficiency and Cystic Fibrosis.

Last and perhaps one of the most exciting applications of CRISPR in drug discovery is the potential to create highly sensitive, inexpensive, point‐of‐care diagnostics for the early detection of disease (Chen et al. 2018; Gootenberg et al. 2018; Myhrvold et al. 2018). It is widely accepted, particularly in Oncology, that the probability of patient survival from the disease increases with early disease detection. The creation of diagnostics that detect cancer in stage 1 rather than when symptomatic in stage 3 or 4 will transform our ability to treat and perhaps cure this disease. Two methods have been published, described as SHERLOCK and DETECTR, that offer the potential to create such sensitive DNA diagnostics. While in early development, the potential of these innovations is huge and are being applied more broadly, including for the creation of a diagnostic test for the SARS‐CoV2 virus.

Since the demonstration of the ability of CRISPR/Cas systems to precisely and efficiently edit gene sequences in 2012, CRISPR has become embedded as a routine technique in molecular and cell biology laboratories across the field. New industries have been created to supply CRISPR reagents and CRISPR‐edited cell and animal models to the research scientist, to develop CRISPR medicines and to create CRISPR diagnostics. The applications and impact of CRISPR in drug discovery are discussed at length within this book. Within eight short years, CRISPR has transformed our ability to identify and characterize the role of new drug targets in disease and to create the cell and animal models integral to identify and optimize drug candidates. With the rate of innovation in this field, we can look forward to the development of novel CRISPR systems that increase the efficiency and specificity of gene editing, to the development of transformative CRISPR therapies with the potential to cure severe genetic diseases and to the invention of highly sensitive diagnostics for the early identification and subsequent cure of many common diseases. As we move through the coming decades, the opportunity for CRISPR to improve human health remains enormous.

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