Validating therapeutic targets through human genetics View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-08

AUTHORS

Robert M. Plenge, Edward M. Scolnick, David Altshuler

ABSTRACT

More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' - naturally occurring mutations in humans that affect the activity of a particular protein target or targets - can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose-response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug-gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics. More... »

PAGES

581-594

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    http://scigraph.springernature.com/pub.10.1038/nrd4051

    DOI

    http://dx.doi.org/10.1038/nrd4051

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1032079011

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/23868113


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