Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation

Sermet‐Gaudelus, Isabelle

doi:10.1183/09059180.00008512

Cited by 45 publications

(33 citation statements)

References 26 publications

(44 reference statements)

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“…Similar effects with an overall improvement of FEV1 % pred of 12.5% were observed in younger CF patients (6-11 years of age) with a G551D mutation, and it was shown that ivacaftor improves the lung clearance index in children with CF with normal spirometry [64,66]. While it remains to be seen to what extent these therapeutic benefits on pulmonary function are cumulative to already existing symptomatic therapies [67][68][69][70], this breakthrough provides an important proof-of-concept that mutation-specific therapy is possible and may, therefore, mark the beginning of a new era of personalised medicine for CF, a topic that has been discussed in several recent reviews [71][72][73]. The CFTR potentiator creates opportunities for personalised medicine for CF However, because the G551D mutation affects only ,4% of CF patients worldwide, considerable challenges remain that need to be overcome before a larger group of patients can benefit from these novel CFTR modulator therapies.…”

Section: Emerging Novel Therapies To Rescue Mutant Cftr: Breakthroughmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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Section: Emerging Novel Therapies To Rescue Mutant Cftr: Breakthroughmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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“…Taken together, these preclinical results suggest that ivacaftor specifically targets and repairs the underlying gating defect caused by the G551D mutation. Based on this evidence clinical trials were commenced in CF patients carrying at least one copy of the G551D-CFTR mutation, the results of which are discussed in the article by SERMET-GAUDELUS [55] [56,57].…”

Section: Cftr Correctorsmentioning

confidence: 99%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

102

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Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

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“…He will also comment on the various classes of CFTR mutations and how they can be targeted by CFTR modulators, as well as briefly examining the proposed mechanisms of action of CFTR modulators before focusing on the pre-clinical development of ivacaftor. SERMET-GAUDELUS [18] will explore the clinical translation of CFTR modulators by reviewing data from ivacaftor clinical trials in CF patients with a specific CFTR mutation called G551D, and conclude by commenting on the potential future impact of CFTR modulators on CF care.…”

Section: Cystic Fibrosis As a Paradigm For Prospective Personalised Dmentioning

confidence: 99%

Personalised medicine for cystic fibrosis: treating the basic defect

Elborn¹

2013

European Respiratory Review

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Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation

Cited by 45 publications

References 26 publications

CFTR: cystic fibrosis and beyond

CFTR: cystic fibrosis and beyond

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Personalised medicine for cystic fibrosis: treating the basic defect

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