The role of transcriptome analysis in pre-clinical toxicology.
A major benefit of the genomics revolution in biomedical research has been the establishment of transcriptome analysis as an enabling technology in the drug development process. Nowhere in the realm of drug development has the expectation of the impact of transcriptome analysis been greater than in the area of pre-clinical toxicology. Transcriptome analysis, along with other new high-content data generating technologies, has the potential to radically improve the drug safety assessment process by allowing drug development teams to identify potential toxicity liabilities earlier, and thus proceed only with those molecules that have both efficacy at the target and a low potential for toxicity in the human population. In this review we will briefly describe the major ways in which transcriptome analysis is being applied in the pre-clinical safety assessment process, focusing primarily on four areas where transcriptome analysis has already begun to have impact. These include using transcriptome analysis to: 1) understand mechanisms of toxicity: 2) predict toxicity: 3) develop in vivo and in vitro surrogate models and screens; and, 4) develop toxicity biomarkers. We will close by briefly addressing future trends and needs in the application of transcriptome analysis to drug safety assessment.
Searfoss
George H
GH
Lilly Research Laboratories, Department of Investigative Toxicology, Eli Lilly and Company, Greenfield, IN 46140, USA. searfgh@lilly.com
Ryan
Timothy P
TP
Jolly
Robert A
RA
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015415:Biomarkers; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D023281:Genomics; D006801:Humans; D040081:Protein Array Analysis; D011506:Proteins / Q000032:analysis*; D043922:Toxicogenetics; D014158:Transcription, Genetic
D015415:Biomarkers; D011506:Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human