Plenge Lab
Date posted: February 8, 2013 | Author: | No Comments »

Categories: Drug Discovery Precision Medicine

Genetics can guide the first phase of drug development (identifying drug targets, see here ) as well as late phase clinical trials (e.g., patient segmentation for response/non-responder status, see here ). But is there a convergence between the two areas, or pharmaco-convergence (a term I just made up!)? And are there advantages to a program anchored at both ends in human genetics?


Consider the following two hypothetical examples.

(1) Human genetics identifies loss-of-function (LOF) mutations that protect from disease. The same LOF mutation is associated with an intermediate biomarker, but is not associated with other phenotypes that might be considered adverse drug events. A drug is developed that mimics the effect of the mutation; that is, a drug is developed that inhibits the protein product of the gene. In early mechanistic studies, the drug is shown to influence the intermediate biomarker in a way that is consistent to that predicted by the LOF-protective mutations. Further, because functional studies of the LOF-protective mutations provide insight into relevant biological pathways in humans (e.g., a gene expression signature that correlates with mutation carrier status), additional information is known about genomic signatures of those who carry the LOF-protective mutations (which mimics drug exposure) compared to those who do not carry the LOF-protective mutations (which mimics those who are not exposed to drug).…

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