Drug Discovery
A phenotypic rescue approach - Two applications of CRISPR-Cas9 technology
Fail Early, Fail Fast - A phenotypic rescue approach

Fail Early, Fail Fast - A phenotypic rescue approach

By Dr Anne-Marie Zuurmond, et al.

New disease targets frequently emerge in literature, but the thorough target validation required to consider these targets for a drug discovery programme is often lacking.

In pharmacological or genetic perturbation studies using complex biological assays, undesired off-target effects cannot be easily distinguished from the intended mode of action at the desired target. This is especially evident in cancer drug development where it is important to discriminate on-target effects on cell viability from off-target effects resulting in non-specific loss of cellular fitness. Neglecting the possibility of being deceived by off-target effects can have tremendous scientific and financial impact on a drug discovery programme. Ideally confidence in a preclinical drug target and a modulating compound is boosted in an early stage by more extensive analysis and validation of the actual target-disease or drug-target relationship. Rescue of a relevant phenotype by genetic restoration of a target mutation is a gold standard approach in drug discovery by which target validation can be achieved.

The cost of failure in drug development

Drug development is a cost and time-consuming process that can take more than 12 years (1) and cost about US$2.6 billion per approved compound (2). Such big figures are associated with high risks for the party investing in a drug development programme for which it is crucial to mitigate the chance of failure and thereby reduce costs involved as much as possible. However, in practice only about 14% of Phase I drugs reach approval. In oncology specifically, drug attrition rates are even higher, with only a meager 3.4% of drugs being licensed (3), which represents a huge financial burden on a development programme. Discontinuation of drug development projects during clinical trial is often due to poor efficacy or safety, aspects that may be tackled by more thorough characterisation earlier in the pipeline utilising appropriate biological models and target validation approaches. CRISPR-Cas9 technology can be used in a simplified phenotype rescue approach, decreasing the significant pressure on profitability in drug discovery by limiting cost and failure as early as the target validation step.

Common target identification, hit finding and validation approaches

Currently the identification of a druggable target (gene, mRNA or protein) associated with a disease phenotype relies mainly on functional genomics and phenotypic screenings. For example, data generated by genome sequencing of individuals, tissues and cancers are great resources to identify genomic characteristics, gene mutations or genetic factors associated with disease. Identification of a biological target has also benefited from the advances in functional genomic screening, such as RNA interference and CRISPR-Cas9 systems, high-throughput phenotypic screens using libraries of small molecules, biologics (antibodies and enzymes) and TIDES (peptides and oligonucleotides) are key to the identification of moieties that induce a desired therapeutic effect in a specific disease model. Also in silico analysis of drugtarget interaction is valuable for tool compound prediction and lead optimisation. Altogether these target identification and hit finding approaches are the very first steps in a drug development pipeline....

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