Application of pharmacogenomics and bioinformatics to exemplify the utility of human ex vivo organoculture models in the field of precision medicine

• Published in: PloS one 2019-12, Vol.14 (12), p.e0226564-e0226564
• Main Authors: Cowan, Karen, Macluskie, Graeme, Finch, Michael, Palmer, Colin N A, Hair, Jane, Bylesjo, Max, Lynagh, Sarah, Brankin, Pamela, McNeil, Marian, Low, Carolyn, Mallinson, David, Gourlay, Elaine M, Child, Hannah, Cheyne, Linda, Bunton, David C
• Format: Article
• Language: English
• Subjects: Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Benzamides - pharmacology; Benzamides - therapeutic use; Bioinformatics; Biology and life sciences; Biopsy; Capital costs; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; Clinical trials; Collaboration; Computational biology; Cyclopropanes - pharmacology; Cyclopropanes - therapeutic use; Cytochrome P-450; Cytokines; Development strategies; Disease; Drug efficacy; Drugs; Fluticasone - pharmacology; Fluticasone - therapeutic use; Formoterol Fumarate - pharmacology; Formoterol Fumarate - therapeutic use; Genes; Genetic diversity; Genomics; Genomics - methods; Genotype & phenotype; Genotypes; Hospitals; Humans; Inflammation; Lung - chemistry; Lung - drug effects; Lung - growth & development; Lung diseases; Medical research; Medicine; Medicine and Health Sciences; MicroRNA; MicroRNAs - genetics; miRNA; Models, Biological; Obstructive lung disease; Organ Culture Techniques - methods; Patients; Pharmacogenomic Variants; Pharmacogenomics; Pharmacology; Physiology; Precision Medicine; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - genetics; R&D; Research & development; Research and Analysis Methods; Ribonucleic acid; RNA; Roflumilast; Smad3 protein; Socialized medicine; State Medicine; Test systems; Whole Exome Sequencing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0226564

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response.