Abstract
The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs—for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.
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Acknowledgements
The authors thank B. Dalton, P. Gros, H. Hobbs, R. McInnes, D. Roden, R. Touyz and G. Waeber for their careful reading of the manuscript and their advice. This work was supported by the McGill Canada Excellence Research Chair Program in Genomic Medicine.
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K.T. and V.M. planned and co-wrote the manuscript and conceptualized and designed the figures and tables. C.B., D.T., S.Z. and J.B.R. provided conceptual input and edited and revised the manuscript.
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V.M. has received honoraria from DalGene and shares from MedeLoop. J.B.R. is the founder of 5 Prime Sciences, has served as a consultant to GlaxoSmithKline and Deerfield Capital for their genetics programmes and has received shares from MedeLoop. The other authors declare no competing interests.
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Trajanoska, K., Bhérer, C., Taliun, D. et al. From target discovery to clinical drug development with human genetics. Nature 620, 737–745 (2023). https://doi.org/10.1038/s41586-023-06388-8
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DOI: https://doi.org/10.1038/s41586-023-06388-8
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