Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Middleton, Peter G.; Mall, Marcus; Dřevı́nek, Pavel; Lands, Larry C.; McKone, Edward F.; Polineni, Deepika; Ramsey, Bonnie W.; Taylor‐Cousar, Jennifer L.; Tullis, Elizabeth; Vermeulen, François; Marigowda, Gautham; McKee, Charlotte M.; Moskowitz, Samuel M.; Nair, Nitin; Savage, J. R. K.; Simard, C; Tian, Simon; Waltz, David A.; Xuan, Fengjuan; Rowe, Steven M.; Jain, Raksha

doi:10.1056/nejmoa1908639

Cited by 1,321 publications

(1,242 citation statements)

References 32 publications

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“…Even though patients affected by CF have found therapies in molecules that help correct mutant-CFTR malfunctions (Heijerman et al, 2019;Middleton et al, 2019), and new such molecules are being discovered (Pedemonte et al, 2020), almost 10% of CF patients are still left with no such treatment. The potential use of KCa3.1 inhibitors correspond to what has been called a "mutationagnostic" treatment for CF, but also seems suitable for easing other muco-obstructive diseases affecting humans.…”

Section: Discussionmentioning

confidence: 99%

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Vega

Guequén

Philp

et al. 2020

Preprint

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Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping the airways free of infection and mucus obstruction. Airways surface liquid (ASL) volume, ciliary beating and mucus are central for proper MCC, and are critically regulated by sodium (Na + ) absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive disease. The calcium-activated potassium (K + )channel KCa.3.1, encoded by the Kcnn4 gene, participates in intestinal ion secretion and previous studies showed that its activation increase Na + absorption in airway epithelia, suggesting that hyperpolarization induced by KCa3.1 was sufficient to drive Na + absorption.However, its role in airway epithelial function is not fully understood. We therefore aimed to elucidate the role of KCa3.1 in MCC in a genetically engineered mouse model. We show that KCa3.1 inhibition reduced Na + absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency (CBF) and MCC ex vivo and in vivo.Kcnn4 was silenced in the Scnn1b-transgenic mouse (Scnn1b tg/+ ), a model of muco-obstructive lung disease triggered by increased epithelial Na + -absorption, leading to improvements in MCC and reduction of Na + -absorption. KCa3.1 deletion did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1b tg/+ mice. K + -channel modulation may be a novel therapeutic strategy to treat muco-obstuctive lung diseases.

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Section: Discussionmentioning

confidence: 99%

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Vega

Guequén

Philp

et al. 2020

Preprint

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“…KEEP PATIENTS OUT OF THE HOSPITAL Elexacaftor-tezacaftor-ivacaftor, approved by the US Food and Drug Administration on October 31, 2019, has resulted in a signifi cant reduction in pulmonary exacerbations in CF. 1 Anecdotally, CF centers throughout the United States have noticed fewer hospital admissions since its introduction, and this is particularly benefi cial to CF patients during the COVID-19 pandemic.…”

Section: ■ Strategies For Outpatient Managementmentioning

confidence: 99%

Keep cystic fibrosis patients out of the hospital

Dasenbrook

2020

CCJM

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“…Particularly with the recent approval of highlyeffective CFTR modulator therapy, future examination of eradication protocols without rifampin will be of increased importance so as to not diminish the effect of this modulator therapy on clinical outcomes for nearly 90% of our patients. 18 This retrospective study of real-world MRSA eradication outcomes utilizing the STAR-too trial protocol in children shows that eradication may lead to a sustained increase in culture negativity, but there may be no significant effect of eradication on clinical outcomes. However, the small sample size of this single-center study limits the interpretation and application of these findings to all children with CF.…”

Section: Discussionmentioning

confidence: 91%

Outcomes of a methicillin‐resistant Staphylococcus aureus (MRSA) eradication protocol in pediatric cystic fibrosis (CF) patients

Belarski

Pettit

2020

Pediatric Pulmonology

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Objective Methicillin‐resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients have greatly increased in prevalence in the past two decades and may lead to a more rapid rate of lung function decline. The objective of this study was to determine the impact of a MRSA eradication protocol on long‐term culture results and clinical outcomes of pediatric CF patients in a real‐world setting. Methods This was a single‐center, retrospective study of children age 30 days to 17 years. Eradication followed the STAR‐too study protocol. The primary outcome was the percent of patients with MRSA‐negative cultures at 12 months. Secondary outcomes were the percent of patients with negative cultures at 3, 6, and greater than 12 months and changes in clinical outcomes compared to individual baseline. Results Of the 55 patients who met inclusion criteria, 10 received protocol eradication. Baseline characteristics were similar between eradication and control groups except more eradication patients were on ivacaftor (30% vs 4%; P = .037). Two eradication patients did not receive rifampin due to ivacaftor use. Eradication did not significantly increase the percent of MRSA‐negative cultures at 3 months (P = .122), 6 months (P = .058), or 12 months (P = .108); however, did increase culture negativity at greater than 12 months (P = .008). Eradication resulted in no significant differences in clinical outcomes compared to control. Conclusions An extensive eradication protocol may lead to an increased clearance rate of long‐term CF respiratory cultures but does not appear to affect clinical outcomes. Eradication may be reasonable to attempt; however, more data is needed before routine recommendation in all patients.

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Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Cited by 1,321 publications

References 32 publications

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Keep cystic fibrosis patients out of the hospital

Outcomes of a methicillin‐resistant Staphylococcus aureus (MRSA) eradication protocol in pediatric cystic fibrosis (CF) patients

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