Abstract
Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders. In this pilot study, we show how multiscale differential dynamic microscopy (multi-DDM) can be used to characterize collective ciliary beating in a non-biased automated manner. We use multi-DDM to assess the efficacy of different CFTR-modulating drugs in human airway epithelial cells derived from subjects with cystic fibrosis (ΔF508/ΔF508 and ∆F508/-) based on ciliary beat frequency and coordination. Similar to clinical observations, drug efficacy is variable across donors, even within the same genotype. We show how our assay can quantitatively identify the most efficient drugs for restoring ciliary beating for each individual donor. Multi-DDM provides insight into ciliary beating responses following treatment with drugs, and has application in the broader context of respiratory disease and for drug screening.
Highlights
Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders
We perform multi-differential dynamic microscopy (DDM) analysis and show that primary human airway epithelial cells (HAECs) obtained from subjects with the ΔF508/ΔF508 CFTR genotype exhibit unique cilia coordination and ciliary beat frequency (CBF) dynamics compared to cells from healthy subjects
One of the first parameters normally probed in clinical samples of HAECs, and one which is a general indication of ciliary function, is the CBF
Summary
Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders. Multi-DDM data directly quantify the loss of cilia coordination with distance, and how this phenotype is affected by mucus properties in both direct perturbations and pharmacological intervention, providing important information about coordination of cilia dynamics in the context of CF We apply this approach in a pilot study to assess donor-to-donor variability in response to different CFTR-modulating drugs, the combination of VX-770 (ivacaftor/KALYDECO®) and VX-809 (lumacaftor, together termed ORKAMBI®), as well as C4, C18 and various combinations thereof. Our multi-DDM-based analyses identify the specific drug(s) that best restores collective ciliary beating dynamics for a given donor culture in vitro and may be a useful screening tool to predict drug efficacy in vivo in a personalised manner These data represent an in-depth, quantitative assessment of cilia coordination in HAECs derived from subjects with CF and how coordination changes in response to CFTRmodulating drugs. This study applies multi-DDM analysis to investigate ciliary beating dynamics in the context of CF, our approach to phenotyping cilia dynamics could be applied to the other respiratory diseases in which ciliary beating is affected
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