2.2.2 Target Validation

Target validation is the process of establishing that modulating a candidate target actually alters the disease phenotype in a therapeutically favourable...

Target validation is the process of establishing that modulating a candidate target actually alters the disease phenotype in a therapeutically favourable direction, and is as important scientifically as identification itself. Common validation approaches include genetic knockdown (using RNA interference or antisense oligonucleotides to transiently reduce target expression), genetic knockout (using CRISPR-Cas9 or older recombination-based techniques to eliminate the gene entirely, typically in an animal model), and pharmacological probe studies, in which a well-characterised tool compound is used to modulate the target acutely and observe the resulting phenotype. A poorly validated target is among the most common causes of late-stage clinical failure: a drug can be highly potent and selective against its intended target and still show no clinical benefit if that target was never truly disease-driving in humans, a phenomenon sometimes termed the 'right drug, wrong target' failure mode. For this reason, contemporary drug-discovery organisations increasingly demand convergent evidence from human genetics, disease-tissue expression data, and pharmacological probe studies before committing substantial resources to a target.