WS14.1 Ivacaftor potentiates mutant CFTR forms associated with residual CFTR function

Objectives: Clinical studies have shown that ivacaftor, an oral CFTR potentiator, increased CFTR channel activity and improved lung function in patients with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate whether ivacaftor potentiates mutant CFTR with non-gating CFTR channel defects. Methods: The pharmacological action of ivacaftor on over 50 mutant CFTR forms was evaluated in electrophysiological studies using a panel of Fischer rat thyroid cells or human bronchial epithelia cells isolated from patients with CF. Results: Ivacaftor potentiated multiple mutant CFTR forms that deliver sufficient amounts of functional CFTR to the cell surface to result in residual baseline chloride transport. These included CFTR mutations that result in mild defects in CFTR processing and delivery to the cell surface, reduced channel conductance, or reduced CFTR synthesis. In addition, ivacaftor also potentiated mutant CFTR forms that result in residual chloride transport due to defects in both channel gating activity and channel conductance, such as R117H-CFTR. Single-channel studies indicated that ivacaftor increased the channel open probability of R117H-CFTR to enhance chloride transport. In contrast, a minimal ivacaftor response was observed in cells expressing mutant CFTR forms associated with minimal baseline chloride transport. Conclusions: This in vitro study indicated that ivacaftor acts on multiple mutant CFTR forms with defects beyond channel gating and supports investigation of the potential clinical benefit of ivacaftor in patients with CF who have cell surface CFTR that results in residual chloride transport. Sponsored by Vertex.