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

Kopp, Benjamin T.; Fitch, James; Jaramillo, Lisa; Shrestha, Chandra L.; Robledo‐Avila, Frank; Zhang, Shuzhong; Palacios, Sabrina; Woodley, Fred; Hayes, Don; Partida-Sánchez, Santiago; Ramilo, Octavio; White, Peter; Mejías, Asunción

doi:10.1016/j.jcf.2019.08.021

Cited by 37 publications

(40 citation statements)

References 44 publications

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“…Treatment with Orkambi ® or Symdeko ® yielded no significant modification of the urinary exosome proteomic content. Our data contrast with recently published transcriptomic studies which identified 36 genes significantly modified after Orkambi ® treatment [33]. Although this number is small at the genome scale, suggesting that these drugs may have only a very limited effect on transcription, the results highlighted modifications of relevant pathways in the context of CFTR, such as normalization of protein synthesis, decreased expression of cell-death genes, and in clinical responders, changes in oxidative phosphorylation, mitochondrial function, eIF2 and IL-17 signaling.…”

Section: No Evidence Of Strong Proteomic Modulation By Cftr Modulatorscontrasting

confidence: 99%

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

Gauthier

Pranke

Jung

et al. 2020

IJMS

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Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.

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Section: No Evidence Of Strong Proteomic Modulation By Cftr Modulatorscontrasting

confidence: 99%

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

Gauthier

Pranke

Jung

et al. 2020

IJMS

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“…In a different study, transcriptomic RNA sequencing (RNAseq) was carried out in whole blood from patients with CF, and 491 genes were found to be differentially expressed as compared to non-CF controls, with further validation of the most overexpressed genes, MMP9 and SOCS3 by qPCR [180]. It has been shown that monocytes from patients with CF have increased expression of MMP9, associated with increased intracellular Ca 2+ when compared with non-CF monocytes [180,181]; remarkably, monocytes with from CF patients treated with Ivacaftor/ Lumacaftor showed reduced intracellular Ca 2+ levels [180]. Finally, a recent study showed that overexpression of PD-L1 in monocytes with CF mutations, was associated with P. aeruginosa infections in patients with CF [182]; furthermore, not only PD-L1 was increased in the CF monocytes, but also the levels of sPD-L1 were increased in the plasma of these patients, as well as PD-1 in both CD4 + and CD8 + T cells [182].…”

Section: Monocytesmentioning

confidence: 99%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

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Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

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“…In addition to improving inflammation through moderating host responses, CFTR modulators may have direct anti-inflammatory effects. A recent study showed that IVA/TEZ and IVA/LUM combination therapies not only reduced levels of pro-inflammatory cytokines but also increased levels of the anti-inflammatory IL-10 [ 119 ]. Furthermore, IVA has recently been shown to increase NO levels in a small group of CF patients with sino-nasal disease [ 147 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, a recent study by Jarosz-Griffiths et al examined the inflammatory effects of CFTR modulators in monocytes isolated from clinically stable patients homozygous for Phe508del CF mutation [ 119 ]. Using LPS/ATP stimulation to activate NLRP3, they reported a reduction in IL-18 following the in vitro application of ivacaftor/lumacaftor (IVA/LUM) and ivacaftor/tezacaftor (IVA/TEZ), but a reduction in IL-1β levels was found only with IVA/TEZ.…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

“…Similarly, after three months of patient treatment, LPS-ATP stimulated the secretion of IL-1β remained unchanged in cells exposed in vivo to IVA/LUM, but it was significantly reduced in cells from patients receiving IVA/TEZ. Furthermore, IL-10 levels were increased in both studies, suggesting that CFTR modulator combinations exhibit anti-inflammatory effects [ 119 ].…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

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Airway Inflammation and Host Responses in the Era of CFTR Modulators

Keown

Brown

Doherty

et al. 2020

IJMS

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The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

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

Cited by 37 publications

References 44 publications

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Airway Inflammation and Host Responses in the Era of CFTR Modulators

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