Early-stage R&D for drug discovery based on human genetics

More than 90% of compounds that enter clinical trials fail to demonstrate safety and efficacy in human populations.  Most of this failure is due to the limited predictive value of pre-clinical models of disease, and our continued ignorance of the consequences of perturbing specific targets over long periods of time in humans.  “Experiments of nature” can be used to generate and validate therapeutic hypotheses for drug discovery based on human in vivo observation, as well as establish causal rather than reactive relationships between targets and outcomes. In our lab, we argue that experiments of nature – and especially human genetic variation associated with clinical phenotypes – should occupy a prominent position in the hierarchy of pre-clinical models for target validation.   We have ongoing projects to use human genetics to develop high-throughput assays that recapitulate the biology of underlying mutations, in order to perform small molecular drug screens.  Further, we use computational tools to link genetic findings with existing databases of drugs to facilitate drug repurposing.

This is an emerging component of our lab – to date, we have conducted only one small drug screen (of the CD40 signaling pathway).  However, we expect that as our genetic studies point to novel biological pathways and our immunogenomic studies uncover the functional consequences of risk alleles, that we will expand our drug discovery projects.