Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis

Autor: Frank Robledo-Avila, Don Hayes, Lisa Jaramillo, Asuncion Mejias, Shuzhong Zhang, Sabrina Palacios, Santiago Partida-Sanchez, Peter White, James Fitch, Benjamin T. Kopp, Chandra L. Shrestha, Octavio Ramilo, Fred Woodley
Rok vydání: 2020
Předmět:
Adult
Male
0301 basic medicine
Pulmonary and Respiratory Medicine
Cystic Fibrosis
Pharmacogenomic Variants
Aminopyridines
Cystic Fibrosis Transmembrane Conductance Regulator
Quinolones
Pharmacology
Aminophenols
Cystic fibrosis
Biomarkers
Pharmacological
Article
Transcriptome
Ivacaftor
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Gene expression
Humans
Metabolomics
Medicine
Benzodioxoles
SOCS3
Chloride Channel Agonists
Ion Transport
biology
business.industry
Homozygote
Lumacaftor
Prognosis
medicine.disease
Cystic fibrosis transmembrane conductance regulator
Pharmacogenomic Testing
Drug Combinations
030104 developmental biology
030228 respiratory system
chemistry
Mutation
Pediatrics
Perinatology and Child Health
biology.protein
Female
Annexin A3
business
Biomarkers
medicine.drug
Zdroj: J Cyst Fibros
ISSN: 1569-1993
DOI: 10.1016/j.jcf.2019.08.021
Popis: Background Cystic fibrosis (CF) remains without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR variant p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response. Methods Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation of gene expression with clinical variables was performed by stratification via clinical responses. Results We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls and 36 genes when comparing pre-drug to post-drug profiles. Both pre- and post-drug CF profiles were associated with marked overexpression of inflammation-related genes and apoptosis genes, and significant under-expression of T cell and NK cell-related genes compared to non-CF. CF patients post-drug demonstrated normalized protein synthesis expression, and decreased expression of cell-death genes compared to pre-drug profiles, irrespective of clinical response. However, CF clinical responders demonstrated changes in eIF2 signaling, oxidative phosphorylation, IL-17 signaling, and mitochondrial function compared to non-responders. Top overexpressed genes (MMP9 and SOCS3) that decreased post-drug were validated by qRT-PCR. Functional assays demonstrated that CF monocytes normalized calcium (increases MMP9 expression) concentrations post-drug. Conclusions Transcriptomics revealed differentially regulated pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor.
Databáze: OpenAIRE
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