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Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic and heterogeneous disorder characterized by remitting and relapsing periods of activity. Pharmacogenetics refers to the study of the effect of inheritance on individual variation in drug responses. Several drug-related markers in IBD patients have been identified in order to predict the response to medical treatment including biological therapy as well as the reduction of adverse events. In the future, the treatment of IBD should be personalized in its specific profile to provide the most efficacious treatment with lack of adverse events.

SUBMITTER: Yamamoto-Furusho JK

PROVIDER: S-EPMC5457182 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

Yamamoto-Furusho Jesús K JK

Pharmacogenomics and personalized medicine 20170526

Inflammatory bowel disease (IBD) is a chronic and heterogeneous disorder characterized by remitting and relapsing periods of activity. Pharmacogenetics refers to the study of the effect of inheritance on individual variation in drug responses. Several drug-related markers in IBD patients have been identified in order to predict the response to medical treatment including biological therapy as well as the reduction of adverse events. In the future, the treatment of IBD should be personalized in i ...[more]

PMID: 28603427

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Project description:ObjectivesInterleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD).MethodsCandidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2(-/-)) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients.ResultsWe identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3? (REG), REG3?, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3?/?; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls.ConclusionsThese studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.Clinical and Translational Gastroenterology (2012) 3, e10; doi:10.1038/ctg.2012.2; published online 16 February 2012.

Dataset Information

Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

Publications

Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

Similar Datasets

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