Drug development in the era of precision medicine

• Published in: Nature reviews. Drug discovery Vol. 17; no. 3; pp. 183 - 196
• Main Authors: Dugger, Sarah A., Platt, Adam, Goldstein, David B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2018; Nature Publishing Group
• Subjects: 631/154; 631/208/721; 631/208/727/2000; 692/699/375/178; Biomedicine; Biotechnology; Cancer Research; Drug Development; Drug discovery; Genomics; Genomics - methods; Humans; Medicinal Chemistry; Molecular Medicine; Neoplasms - drug therapy; Pharmaceutical Preparations - chemistry; Pharmacology/Toxicology; Precision Medicine; Rare Diseases - drug therapy; review-article
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd.2017.226

Key Points Prior efforts using genomics to inform drug discovery (that is, expressed sequencing tag profiling and genome-wide association studies) have yielded an array of potential targets but have encountered difficulty in translating these discoveries into clinically efficacious drugs. Precision medicine marks a new relationship between genomics and drug discovery, one that provides both insights into the mechanisms and potential treatment options of a single patient's disease. Oncology has been the leader in the field of precision medicine, with a multitude of successful examples of targeted treatments and immunotherapies available for a wide range of cancers. Precision therapies for Mendelian diseases, such as those that replace deficient proteins, directly target the dysfunctional protein or disease-associated pathway or influence expression of disease-relevant genes, and are clinically available for a number of conditions, such as lysosomal storage disorders, cystic fibrosis, tuberous sclerosis and spinal muscular atrophy. With various reliable model systems and a multitude of drug screening platforms, epilepsy is well positioned to serve as a model for precision medicine in highly genetic conditions. Although it is currently uncertain how generalizable genomic precision medicine approaches will be for all diseases, we imagine that some therapeutics that were developed for defined genetic conditions will also be efficacious in individuals with mechanistically related disease that do not necessarily carry the same genetic drivers. The contribution of genomics to drug discovery and development so far has not yet lived up to the initial high expectations. Goldstein and colleagues discuss the reasons for the limited progress and review how recent advances — particularly in oncology and rare genetic diseases — may enable precision medicine strategies to harness the therapeutic potential of genomic knowledge. For the past three decades, the use of genomics to inform drug discovery and development pipelines has generated both excitement and scepticism. Although earlier efforts successfully identified some new drug targets, the overall clinical efficacy of developed drugs has remained unimpressive, owing in large part to the heterogeneous causes of disease. Recent technological and analytical advances in genomics, however, have now made it possible to rapidly identify and interpret the genetic variation underlying a single patient's disease, thereby providing a window into patient-specific mechanisms that cause or contribute to disease, which could ultimately enable the 'precise' targeting of these mechanisms. Here, we first examine and highlight the successes and limitations of the earlier phases of genomics in drug discovery and development. We then review the current major efforts in precision medicine and discuss the potential broader utility of mechanistically guided treatments going forward.