Sweat chloride as a biomarker of CFTR activity: Proof of concept and ivacaftor clinical trial data

Accurso, Frank J.; Goor, Fredrick Van; Zha, Jiuhong; Stone, Anne J.; Dong, Qunming; Ordoñez, Claudia L.; Rowe, Steven M.; Clancy, John; Konstan, Michael W.; Hoch, Heather; Heltshe, Sonya L.; Ramsey, Bonnie W.; Campbell, Preston W.; Ashlock, Melissa A.

doi:10.1016/j.jcf.2013.09.007

Cited by 120 publications

(105 citation statements)

References 31 publications

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“…Moreover, we did not find any significant correlation between clinical presentation and genetic data, except for an elevated sweat test (which is a biochemical indicator). This is consistent with a previous study [4] and confirms that the sweat test is a useful biomarker of CFTR activity [26]. However, patients with CFTR mutations that were considered in this study as mild or NNV variants (more than 50% of mature CFTR protein produced) showed a slightly higher susceptibility towards lower respiratory capacity (Supplementary table 4).…”

Section: Discussionsupporting

confidence: 92%

Should diffuse bronchiectasis still be considered a CFTR-related disorder?

Bergougnoux

Viart

Miro

et al. 2015

Journal of Cystic Fibrosis

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Section: Discussionsupporting

confidence: 92%

Should diffuse bronchiectasis still be considered a CFTR-related disorder?

Bergougnoux

Viart

Miro

et al. 2015

Journal of Cystic Fibrosis

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“…The combination therapy was effective in significantly reducing sweat chloride levels, a well-representative surrogate marker 64 Figure 6. For figure legend, see page 2066.…”

Section: Discussionmentioning

confidence: 99%

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

et al. 2014

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These authors equally contributed to this work.Keywords: cystic fibrosis, CFTR, autophagy, cysteamine, epigallocatechin gallate, sweat chloride Abbreviations: BECN1/Beclin 1, autophagy-related; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CHX, cycloheximide; CSNK2, casein kinase 2; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL8, chemokine (C-X-C motif) ligand 8; EGCG, epigallocatechin gallate; FEV, forced expiratory volume; PM, plasma membrane; RPD, rectal potential difference; SQSTM1, sequestosome 1; TGM2, transglutaminase 2; TNF, tumor necrosis factor.Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr F508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/ TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

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“…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

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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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Sweat chloride as a biomarker of CFTR activity: Proof of concept and ivacaftor clinical trial data

Cited by 120 publications

References 31 publications

Should diffuse bronchiectasis still be considered a CFTR-related disorder?

Should diffuse bronchiectasis still be considered a CFTR-related disorder?

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

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

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