Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis

To the Editor: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have significantly improved outcomes for people with cystic fibrosis (pwCF), yet those with unresponsive mutations remain without effective treatments. One promising strategy involves enhancing ion channels alternative to CFTR (reviewed in ref. 1), including apically expressed large conductance, calcium-activated potassium (BK) channels. BK channels, composed of the pore-forming subunit KCNMA1 (Slo1) and the regulatory subunit LRRC26 (γ1), are critical for airway surface hydration and mucociliary transport (MCT). Inhibition or knockdown of these components leads to reduced airway surface liquid, increased mucus concentration, and impaired MCT in CF models in vitro and in vivo. BK plays a crucial role in enhancing chloride exit, a phenomenon called apical loop current. Our simulations indicated that small apical increases in potassium conductance (from 0 to 0.002 S/cm2) enhance Cl– efflux approximately 3-fold. Reanalyzing airway single cell RNA-seq data from ref. 4, we show KCNMA1, LRRC26, and ANO1 expression in secretory cells. Among BK β-subunits, only KCNMB2/4 are detected, with KCNMB2 in ciliated cells and KCNMB4 in large airways, supporting the hypothesis that, in peripheral airways where CF disease starts, apical loop currents between ANO1 and BK, made of KCMNA1/LRRC26, can be enhanced therapeutically.