Loss-of-function genetic diseases and the concept of pharmaceutical targets

The biomedical world relies heavily on the definition of pharmaceutical targets as an essential step in the drug design process. It is therefore tempting to apply this model to genetic diseases as well. However, whereas the model applies well to gain-of-function genetic diseases, it is less suited to most loss-of-function genetic diseases. Most common diseases, as well as gain-of-function genetic diseases, are characterized by the activation of specific pathways or the ectopic activity of proteins, which make well identified targets. By contrast, loss-of-function genetic diseases are caused by the impairment of one protein, with potentially distributed consequences. For such diseases, the definition of a pharmaceutical target is less precise, and the identification of pharmaceutically-relevant targets may be difficult. This critical but largely ignored aspect of loss-of-function genetic diseases should be taken into consideration to avoid the commitment of resources to inappropriate strategies in the search for treatments.