Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis

Rowe, Steven M.; Heltshe, Sonya L.; Gonska, Tanja; Donaldson, Scott H.; Borowitz, Drucy; Gelfond, Daniel; Sagel, Scott D.; Khan, Umer; Mayer-Hamblett, Nicole; Dalfsen, Jill M. Van; Joseloff, Elizabeth; Ramsey, Bonnie W.

doi:10.1164/rccm.201404-0703oc

Cited by 453 publications

(486 citation statements)

References 37 publications

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“…Current drugs targeting the mutated CFTR (potentiators/correctors) improve expression and function of CFTR on epithelial surfaces, and patients showed improved lung function and reduced frequency of pulmonary exacerbations, hospitalization, and use of i.v. antibiotics, but augmented CFTR function failed to reduce inflammatory markers in sputum (e.g., IL-1, -6, -8) (26), and heterogeneous responses to the treatment have been reported (27), suggesting that CFTR correction/potentiation may not directly improve the underlying compromised immune response. The negative NF-κB regulator A20 (TNFAIP3) is reduced in CF airway epithelial cells, basally and after LPS stimulation (23), and is associated with markers of inflammation and decreased lung function (12).…”

Section: Discussionmentioning

confidence: 99%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.A20 | NF-κB | connectivity mapping | drug repositioning | CF airway inflammation

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Section: Discussionmentioning

confidence: 99%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In clinical studies, ivacaftor has improved pulmonary function and nutritional status and reduced the number of pulmonary exacerbations, antibiotic use and number of hospital stays. Additionally, improvement in quality of life, mucociliary clearance, gastrointestinal pH, higher levels of exhaled nitric oxide, lower doses of insulin (in diabetics), and fewer infection with Pseudomonas aeruginosa have been observed during ivacaftor treatment [13][14][15][16][17] . Lower sweat chloride concentration has also been clearly documented and the sweat test can be utilized as a marker of compliance with ivacaftor therapy 18 .…”

Section: Discussionmentioning

confidence: 99%

Ivacaftor in cystic fibrosis adults: Czech experience with six years of follow-up

Fila¹,

Bartakova²,

Grandcourtova³

et al. 2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims. Ivacaftor is a revolutionary treatment option for cystic fibrosis (CF) patients with G551D and other gating mutations. The aim of this study was to evaluate the clinical status of patients on ivacaftor who were followed for up to 6 years together with an evaluation of ivacaftor therapy in one patient with an initial FEV 1 less than 40% of predicted value. Methods. Data on development of clinical status and sinopulmonary-related therapies were obtained from patient health records during ivacaftor treatment lasting for up to six years and were compared with an equivalent period before ivacaftor administration. Results. Five CF adults with a median age 28.6 years (range 21.4−35.6 years) with median FEV 1 45% pred. (range 16−85% pred.) were included in the study. Four subjects were also participants in the STRIVE and PERSIST studies. Altogether, twenty-four patient-years of ivacaftor treatment were analyzed. The median FEV 1 decline per year decreased from -4.5 to -0.9% pred. (P = 0.043). Reduction in number of days on antibiotic treatment and hospital stays was 21% (P < 0.001) and 75% (P = 0.003), respectively. Improvement and stabilization of lung function was observed for up to six years of treatment. In a patient with severe airway obstruction, an increase in the FEV 1 value (30.4% from baseline) was documented during the first twelve months of treatment. Conclusion. Ivacaftor therapy resulted in improved and stabilized lung function in up to six years of treatment with a reduction in number of days on antibiotic treatment and hospital stays. Its efficiency was also displayed in a patient with severe airway obstruction.

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“…However, although successfully improving expression and function of CFTR, airway inflammation was not reduced. In CF patients aged 6 years and above with Gly551Asp-CFTR, 6 months of treatment with Ivacaftor did not reduce inflammatory markers in sputum such as IL-1, IL-6 and IL-8 [7] and heterogeneous responses to the corrector/potentiator treatment have been reported in patients homozygous for Phe508del-CFTR [8]. This suggests that CFTR correction/potentiation may not directly improve the underlying compromised immune response, thus there is still an unmet need to normalise the inflammatory response in CF airways.…”

Section: Introductionmentioning

confidence: 83%

Chronic Inflammation in CF Airways - A Persistent Issue for A20

McCallum¹,

A²,

Ennis³

et al. 2016

J Genet Syndr Gene Ther

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Cystic Fibrosis (CF) is characterised by prolonged and exaggerated airways inflammation. Despite recent developments to overcome the underlying functional defect in CFTR (cystic fibrosis transmembrane conductance regulator); there is still an unmet need to reduce the inflammatory response. The NF-κB regulator A20 is a key target to normalise the inflammatory response and is reduced in CF. Here, we describe the plethora of functions of A20 as they apply to innate immune function within the airways. Pharmacological compounds can enhance A20 mRNA and protein expression, but we observed a blunted effect in CF primary epithelial cells. In CF cells pre-treatment with gibberellic acid (GA3) shows anti-inflammatory effects only in some patients. We show that cells with higher basal p38 expression respond with an increase in pro-inflammatory cytokines. Furthermore, all CF PNECs show increased p38 mRNA when stimulated in the presence of GA3. Our results suggest that those patients may benefit from therapeutics targeting p38.

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Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis

Cited by 453 publications

References 37 publications

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Ivacaftor in cystic fibrosis adults: Czech experience with six years of follow-up

Chronic Inflammation in CF Airways - A Persistent Issue for A20

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