Comparison of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Ciliary Beat Frequency Activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in Primary Sinonasal Epithelial Cultures | Adolescent Medicine | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Original Investigation
August 2013

Comparison of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Ciliary Beat Frequency Activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in Primary Sinonasal Epithelial Cultures

Author Affiliations
  • 1Division of Otolaryngology, Department of Surgery, University of Alabama at Birmingham, Birmingham
  • 2Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham
  • 3Department of Medicine, University of Alabama at Birmingham, Birmingham
JAMA Otolaryngol Head Neck Surg. 2013;139(8):822-827. doi:10.1001/jamaoto.2013.3917

Importance  Pharmacologic activation of mucociliary clearance (MCC) represents an emerging therapeutic strategy for patients with chronic rhinosinusitis, even in the absence of congenital mutations of the CFTR gene. Drug discovery efforts have identified small molecules that activate the cystic fibrosis transmembrane conductance regulator (CFTR), including potentiators under development for treatment of cystic fibrosis.

Objective  To evaluate the properties of CFTR modulators and their effects on ciliary beat frequency (CBF) in human sinonasal epithelium (HSNE).

Design  Primary HSNE cultures (wild type and F508del/F508del) were used to compare stimulation of CFTR-mediated Cl conductance and CBF by the CFTR modulators genistein, VRT-532, and UCCF-152.

Main Outcomes and Measures  Increase in CFTR-dependent anion transport and CBF.

Results  HSNE cultures were analyzed using pharmacologic manipulation of ion transport (change in short-circuit current [∆ISC]) and high-speed digital imaging (CBF). Activation of CFTR-dependent anion transport was significantly different among agonists (P < .001), with genistein exerting the greatest effect (mean [SD] ∆ISC, genistein, 23.1 [1.8] μA/cm2 > VRT-532, 8.1 [1.0] μA/cm2 > UCCF-152, 3.4 [1.4] μA/cm2 > control, 0.7 [0.2] μA/cm2; Tukey-Kramer P < .05) in the absence of forskolin. Genistein and UCCF-152 augmented CBF (under submerged conditions) significantly better (Tukey-Kramer P < .05) than cells treated with VRT-532 or dimethyl sulfoxide vehicle control (mean [SD] fold change over baseline, genistein, 1.63 [0.06]; UCCF-152, 1.56 [0.06]; VRT-532, 1.38 [0.08]; control, 1.27 [0.02]). Activation of CBF was blunted in F508del/F508del HSNE cultures.

Conclusions and Relevance  The degree of CBF stimulation was not dependent on the magnitude of Cl secretion, suggesting that different mechanisms of action may underlie MCC activation by these small molecule potentiators. Agents that activate both CFTR-dependent ISC and CBF are particularly attractive as therapeutics because they may address 2 independent pathways that contribute to deficient MCC in chronic rhinosinusitis.