Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi®) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells

Favia, Maria; Gallo, Crescenzio; Guerra, Lorenzo; Venuto, D. De; Diana, Anna; Polizzi, Angela; Montemurro, P.; Mariggiò, Maria Addolorata; Leonetti, G; Manca, Antonio; Casavola, Valeria; Conese, Massimo

doi:10.3390/ijms21072398

Cited by 20 publications

(28 citation statements)

References 36 publications

(51 reference statements)

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“…Reduced bacterial diversity in PWCF is typically associated with increasing age; however, young children with CF have decreased airway microbial diversity compared to healthy children of the same age [ 148 ]. In children with CF, modulators have been shown to improve bacterial diversity to a state similar to that of healthy individuals (IVA and TEZ/IVA) [ 149 ], with similar findings in adults with the G551D mutation taking IVA [ 117 , 118 , 150 ]. However, only small numbers of patients have been studied, and as established microbial communities may take time to adjust, larger longitudinal microbiome studies are needed to assess the long-term effects on the microbiome.…”

Section: Cftr Modulators the Microbiome And Airway Infectionmentioning

confidence: 87%

“…Ex vivo studies have revealed direct effects of CFTR modulators on the function of neutrophils [ 69 , 109 , 124 , 125 ], macrophages [ 126 , 127 , 130 ], lymphocytes [ 131 , 132 , 133 ], epithelial cells [ 134 , 135 ], and their signalling pathways [ 124 , 128 , 132 ]. There have been additional effects of CFTR modulators demonstrating improvements in MCC including LCI, mucus plugging, and air trapping [ 117 , 121 , 122 ], as well as effects on ciliary function [ 143 ]. However, despite these findings, uncertainty remains as to whether these effects are directly attributable to modulator effects on target cells or whether they are secondary to modification of the diseased airway environment.…”

Section: Discussionmentioning

confidence: 99%

“…Hisert et al demonstrated that sputum inflammatory markers decreased significantly in the first week of IVA treatment in patients with G551D mutations, with a continued decline in IL-8, IL-1β, and NE over the subsequent two years [ 117 ]. These improvements were accompanied by clinical improvements in FEV 1 and mucus plugging on high-resolution CT (HRCT).…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

“…Furthermore, it is unclear whether observed effects are due to directly improved host responses or through general improvement of the airway environment. Indeed, patients with the G551D mutation showed marked improvements in whole lung, central, and peripheral MCC at 1 and 3 months after starting treatment with IVA, which correlated with lung function [ 117 ]. Other studies have shown reductions in lung clearance index (LCI) with CFTR modulation [ 120 ], indicating reduced mucus plugging and improved air trapping [ 121 , 122 ].…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

“…Hisert et al have shown that Pa burden in chronically infected patients fell within 48 h after initiation of IVA, with a 10-fold reduction in density after 7 days [ 117 ]. However, none of the 8 chronically infected patients studied became consistently culture negative, and the Pa density increased again in the second year of treatment.…”

Section: Cftr Modulators the Microbiome And Airway Infectionmentioning

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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Section: Cftr Modulators the Microbiome And Airway Infectionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

Section: Cftr Modulators the Microbiome And Airway Infectionmentioning

confidence: 99%

See 3 more Smart Citations

Airway Inflammation and Host Responses in the Era of CFTR Modulators

Keown

Brown

Doherty

et al. 2020

IJMS

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Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Turton

Ingram

Valvano

2020

Journal of Leukocyte Biology

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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the homeostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respiratory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTR is, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitive to conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophages by affecting the lung milieu, but the mutations also appear to be directly consequential for intrinsic macrophage functions. Particular mutations can alter CFTR's folding, traffic of the protein to the membrane and function. As such, understanding the intrinsic effects of CFTR mutation requires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from the primary defect of CFTR dysfunction/absence. Investigations into CFTR's role in macrophages have exploited various models, each with their own advantages and limitations. This review summarizes these methodologic approaches, discussing their physiological correspondence and highlighting key findings. The controversy surrounding CFTR-dependent acidification is used as a case study to highlight difficulties in commensurability across model systems. Recent work in macrophage biology, including polarization and host-pathogen interaction studies, brought into the context of CFTR research, offers potential explanations for observed discrepancies between studies. Moreover, the rapid advancement of novel gene editing technologies and new macrophage model systems makes this assessment of the field's models and methodologies timely.

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