Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
AAPS J. 2013 Apr;15(2):427-37. doi: 10.1208/s12248-012-9447-1. Epub 2013 Jan 15.
Gene expression is useful for identifying the molecular signature of a disease and for correlating a pharmacodynamic marker with the dose-dependent cellular responses to exposure of a drug. Gene expression offers utility to guide drug discovery by illustrating engagement of the desired cellular pathways/networks, as well as avoidance of acting on the toxicological pathways. Successful employment of gene-expression signatures in the later stages of drug development depends on their linkage to clinically meaningful phenotypic characteristics and requires a biologically meaningful mechanism combined with a stringent statistical rigor. Much of the success in clinical drug development is hinged on predefining the signature genes for their fitness for purposes of application. Specific examples are highlighted to illustrate the breadth and depth of the potential utility of gene-expression signatures in drug discovery and clinical development to targeted therapeutics at the bedside.
基因表达可用于鉴定疾病的分子特征，并将药效标志物与药物暴露引起的剂量依赖性细胞反应相关联。基因表达可用于指导药物发现，说明所期望的细胞途径/网络的参与，以及避免作用于毒理学途径。成功地将基因表达谱应用于药物开发的后期阶段取决于它们与临床有意义的表型特征的关联，并需要结合严格的统计学严谨性的生物学意义上的机制。临床药物开发的大部分成功都取决于为其应用目的预先定义特征基因。突出了具体示例，以说明基因表达谱在药物发现和临床开发中的广泛应用潜力，以及针对床边靶向治疗的潜在应用。
