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

ABSTRACT: 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.

SUBMITTER: Cowan K

PROVIDER: S-EPMC6924641 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Cowan Karen K Macluskie Graeme G Finch Michael M Palmer Colin N A CNA Hair Jane J Bylesjo Max M Lynagh Sarah S Brankin Pamela P McNeil Marian M Low Carolyn C Mallinson David D Gourlay Elaine M EM Child Hannah H Cheyne Linda L Bunton David C DC

PloS one 20191220 12

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 ...[more]

PMID: 31860681

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Project description:BackgroundUnderstanding individual patient host-response to viruses is key to designing optimal personalized therapy. Unsurprisingly, in vivo human experimentation to understand individualized dynamic response of the transcriptome to viruses are rarely studied because of the obvious limitations stemming from ethical considerations of the clinical risk.ObjectiveIn this rhinovirus study, we first hypothesized that ex vivo human cells response to virus can serve as a proxy for otherwise controversial in vivo human experimentation. We further hypothesized that the N-of-1-pathways framework, previously validated in cancer, can be effective in understanding the more subtle individual transcriptomic response to viral infection.MethodN-of-1-pathways computes a significance score for a given list of gene sets at the patient level, using merely the 'omics profiles of two paired samples as input. We extracted the peripheral blood mononuclear cells (PBMC) of four human subjects, aliquoted in two paired samples, one subjected to ex vivo rhinovirus infection. Their dysregulated genes and pathways were then compared to those of 9 human subjects prior and after intranasal inoculation in vivo with rhinovirus. Additionally, we developed the Similarity Venn Diagram, a novel visualization method that goes beyond conventional overlap to show the similarity between two sets of qualitative measures.ResultsWe evaluated the individual N-of-1-pathways results using two established cohort-based methods: GSEA and enrichment of differentially expressed genes. Similarity Venn Diagrams and individual patient ROC curves illustrate and quantify that the in vivo dysregulation is recapitulated ex vivo both at the gene and pathway level (p-values⩽0.004).ConclusionWe established the first evidence that an interpretable dynamic transcriptome metric, conducted as an ex vivo assays for a single subject, has the potential to predict individualized response to infectious disease without the clinical risks otherwise associated to in vivo challenges. These results serve as a foundational work for personalized "virograms".

Dataset Information

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

Publications

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

Similar Datasets

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