Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation.
Steven M. Rowe,Bo Liu,Aubrey E. Hill,Heather Hathorne,Morty Cohen,John R. Beamer,Frank J. Accurso,Qunming Dong,Claudia L. Ordoñez,Anne Stone,Eric R. Olson,John P. Clancy +11 more
TLDR
It is found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects.Abstract:
Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (±2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.read more
Citations
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Journal ArticleDOI
Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis
Deborah M. Cholon,Nancy L. Quinney,M. Leslie Fulcher,Charles R. Esther,Jhuma Das,Nikolay V. Dokholyan,Scott H. Randell,Richard C. Boucher,Martina Gentzsch +8 more
TL;DR: It is found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies, and these findings demonstrate that chronic treatmentWith CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies.
Journal ArticleDOI
“CFTR Modulator Theratyping: Current Status, Gaps and Future Directions”
John P. Clancy,Calvin U. Cotton,Scott H. Donaldson,George M. Solomon,Donald R. VanDevanter,Michael P. Boyle,Martina Gentzsch,Jerry A. Nick,Beate Illek,John C. Wallenburg,Eric J. Sorscher,Margarida D. Amaral,Jeffrey M. Beekman,Anjaparavanda P. Naren,Robert J. Bridges,Philip Thomas,Garry R. Cutting,Steven M. Rowe,Anthony G. Durmowicz,Martin Mense,Kris De Boeck,William R. Skach,Christopher M. Penland,Elizabeth Joseloff,Hermann Bihler,John Mahoney,Drucy Borowitz,Katherine L. Tuggle +27 more
TL;DR: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.
Journal ArticleDOI
Ion Channel Modulators in Cystic Fibrosis
TL;DR: How patient‐derived precision medicine models may aid the translation of emerging next‐generation ion channel modulators from the laboratory to the clinic and tailor their use for optimal therapeutic benefits in individual patients with CF is discussed.
Journal ArticleDOI
Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis.
Simon Y. Graeber,Christian Dopfer,Lutz Naehrlich,Lena Gyulumyan,Heike Scheuermann,Stephanie Hirtz,Sabine Wege,Heimo Mairbäurl,Marie Dorda,Rebecca Hyde,Azadeh Bagheri-Hanson,Claudia Rueckes-Nilges,Sebastian Fischer,Marcus A. Mall,Burkhard Tümmler +14 more
TL;DR: Lumacaftor‐ivacaftors results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations.
Journal ArticleDOI
Combination Therapy with Cystic Fibrosis Transmembrane Conductance Regulator Modulators Augment the Airway Functional Microanatomy
Susan E. Birket,Kengyeh K. Chu,Grace H. Houser,Linbo Liu,Courtney M. Fernandez,George M. Solomon,Vivian Y. Lin,Suresh Shastry,Marina Mazur,Peter A. Sloane,Justin Hanes,William E. Grizzle,Eric J. Sorscher,Guillermo J. Tearney,Steven M. Rowe +14 more
TL;DR: It is established that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen, and improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponding to changes in sweat chloride.
References
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John R. Riordan,Johanna M. Rommens,Batsheva Kerem,Noa Alon,Richard Rozmahel,Zbyszko Grzelczak,Julian Zielenski,Si Lok,Natasa Plavsic,Jia Ling Chou,Mitchell L. Drumm,Michael C. Iannuzzi,Francis S. Collins,Lap-Chee Tsui +13 more
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Cystic Fibrosis
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Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA
TL;DR: A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
Journal ArticleDOI
A CFTR potentiator in patients with cystic fibrosis and the G551D mutation
Bonnie W. Ramsey,Jane C. Davies,N. Gerard McElvaney,Elizabeth Tullis,Scott C. Bell,Pavel Dř evínek,Matthias Griese,Edward F. McKone,Claire E. Wainwright,Michael W. Konstan,Richard B. Moss,Felix Ratjen,Isabelle Sermet-Gaudelus,Steven M. Rowe,Qunming Dong,Sally Rodriguez,Karl Yen,Claudia L. Ordoñez,J. Stuart Elborn +18 more
TL;DR: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks and substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.
Journal ArticleDOI
Effect of VX-770 in Persons with Cystic Fibrosis and the G551D-CFTR Mutation
Frank J. Accurso,Steven M. Rowe,John P. Clancy,Michael P. Boyle,Jordan M. Dunitz,Peter R. Durie,Scott D. Sagel,Douglas B. Hornick,Michael W. Konstan,Scott H. Donaldson,Richard B. Moss,Joseph M. Pilewski,Ronald C. Rubenstein,Ahmet Uluer,Moira L. Aitken,Steven D. Freedman,Lynn M. Rose,Nicole Mayer-Hamblett,Qunming Dong,Jiuhong Zha,Anne Stone,Eric R. Olson,Claudia L. Ordoñez,Preston W. Campbell,Melissa A. Ashlock,Bonnie W. Ramsey +25 more
TL;DR: This study showed that VX-770 was associated with within-subject improvements in CFTR and lung function and provides support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.
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