Target Vaildation Technologies

Once a gene has been identified as a potential therapeutic target, its relevance to a disease process and its suitability as a target should be validated before starting the costly procedure of drug discovery. Target validation involves manipulating the target and confirming that the resulting effect is consistent with purported role. In practice, this is not easy because an infinite number of genes, proteins and other molecules interact with each other in signalling pathways to direct cell function.
Finding a drug target that safely regulates disease without affecting normal function has proved very challenging. Various methods to achieve this are antisense and RNAi (vector-mediated gene inactivation and transient gene inactivation), proteomics, gene expression arrays and combinatorial biology approaches.
1. Animal Models for Genomics-based Target Validation Methods
Animal models of human disease are important for understanding the disease mechanism and for the development and evaluation of new therapies. Some animal models are available where a genetic defect occurs spontaneously. Animal models are invaluable for functional genomic studies. Spontaneously occurring genetic defects in animals are inadequate for serving as models of human disease and thus the need for induced mutations. Mutations can be established in the animal genome by one of two approaches: non-homologous recombinations (transgenic) or homologous recombination (knockout, null mutations).
2. Role of Knockout Mice in Drug Discovery
Most drugs act as inhibitors of their targets. Inactivating a gene in a knockout mouse can mimic the effect of the target’s inhibitor. Mouse functional genomics is similar to that in humans. Thus the knockout mouse defines a drug target and its underlying physiology, permitting an  insight into the disease, its diagnosis and treatment. For example, p53 gene knockouts have been used extensively to investigate tumorigenesis.
The knockout mouse is becoming an invaluable addition to functional genomics-driven drug discovery. There are, however, some reservations about the value of mouse genetics in functional genomics. There are some mutagenesis experiments that result in no phenotype, which may be due to redundancies within the mouse genome or perhaps due to takeover of the function of missing members in certain tissues. This, however, occurs infrequently. If we believe the oft-quoted statement that ‘the first company to show biological relevance in an animal model wins’ in genomic drug development, there is little doubt that the mouse will play an important part in this venture.

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