Pneumologie 2015; 69 - A2
DOI: 10.1055/s-0035-1556594

Intestinal Current Measurements Detect Activation of Mutant CFTR in Cystic Fibrosis Patients with the G551D Mutation Treated with Ivacaftor

S Gräber 1, 2, M Hug 3, O Sommerburg 1, 2, S Hirtz 1, J Hentschel 4, A Heinzmann 5, C Dopfer 6, 7, A Schulz 6, 7, J Mainz 4, B Tümmler 6, 7, MA Mall 1, 2
  • 1Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg
  • 2Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg
  • 3Hospital Pharmacy, University Medical Center Freiburg
  • 4Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics, Jena University Hospital
  • 5Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics, University of Freiburg
  • 6Clinic of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School
  • 7Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover Medical School

Introduction: Recent studies suggest that sensitive outcome measures of in vivo CFTR activity may be important to accelerate clinical development of emerging CFTR modulator therapies for cystic fibrosis (CF). Intestinal current measurements (ICM) detect pharmacological activation of mutant CFTR ex vivo. However, whether ICM can detect rescue of mutant CFTR function in CF patients remains unknown.

Objective: To determine if ICM is sensitive to detect rescue of CFTR Cl- channel function in CF patients with the G551D-CFTR mutation after ivacaftor initiation. Methods: Rectal biopsies were obtained from 37 non-CF controls and 13 CF patients with the G551D mutation before and after initiation of ivacaftor. CFTR Cl- channel function was determined from bioelectric responses to cAMP-dependent stimulation in micro-Ussing chambers.

Measurements and Main Results: Before ivacaftor therapy, ICM detected variable residual cAMP-induced Cl- secretory responses in rectal tissues from G551D CF patients that corresponded to ˜13% of non-CF controls. After ivacaftor initiation, Cl- secretory responses in tissues from G551D CF patients were significantly increased compared to baseline (ΔIsc = 42.7, IQR 27.8 – 63.6µA/cm2; P < 0.001) corresponding to a level of 52% of non-CF controls.

Conclusions: ICM is sensitive to detect in vivo rescue of CFTR function in individual G551D CF patients treated with ivacaftor. These results support the development of ICM as an outcome measure of in vivo rescue of mutant CFTR activity that may facilitate precision medicine with emerging CFTR modulators for CF patients with a spectrum of CFTR mutations including the common mutation F508del.

*Presenting author