In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N-of-1 studies
Meghan E McGarry, Beate Illek, Ngoc P Ly, Lorna Zlock, Sabrina Olshansky, Courtney Moreno, Walter E Finkbeiner, Dennis W Nielson, Meghan E McGarry, Beate Illek, Ngoc P Ly, Lorna Zlock, Sabrina Olshansky, Courtney Moreno, Walter E Finkbeiner, Dennis W Nielson
Abstract
Rationale: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown.
Methods: This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT). Human nasal epithelium (HNE) was obtained via nasal brushing and cultured. Sweat chloride concentration change was the in vivo outcome. Chloride current change in HNE cultures with ivacaftor was the in vitro outcome.
Results: Three subjects had decreased sweat chloride concentration (-14.8 to -40.8 mmol/L, P < 0.01). Two subjects had unchanged sweat chloride concentration. Two subjects had increased sweat chloride concentration (+23.8 and +27.3 mmol/L, P < 0.001); both were heterozygous for A455E and pancreatic sufficient. Only subjects with decreased sweat chloride concentration had increased chloride current in HNE cultures.
Conclusions: Some CF patients with residual CFTR function have decreased sweat chloride concentration with ivacaftor. Increased chloride current in HNE cultures among subjects with decreased sweat chloride concentrations may predict clinical response to ivacaftor. Ivacaftor can increase sweat chloride concentration in certain mutations with unclear clinical effect. Pediatr Pulmonol. 2017;52:472-479. © 2017 Wiley Periodicals, Inc.
Trial registration: ClinicalTrials.gov NCT01784419.
Keywords: CFTR; CFTR modulators; N-of-1 studies; cystic fibrosis; human nasal epithelium; ivacaftor; personalized medicine; sweat chloride concentration.
Conflict of interest statement
Conflicts of Interest
The authors have no conflicts of interest to disclose. The opinions expressed in this article are those of the authors and do not necessarily represent those of the National Institutes of Health, the Cystic Fibrosis Foundation, the Cystic Fibrosis Research, Inc., or the Elizabeth Nash Foundation.
© 2017 Wiley Periodicals, Inc.
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Source: PubMed