For the millions living with chronic respiratory disease rooted in defective cilia, the treatment landscape has long been bleak — no disease-modifying therapies exist. A comprehensive new review in the European Respiratory Review reframes the urgency: advances in genetic medicine are finally within reach, but only if the field builds the right tools to test them.
Primary ciliary dyskinesia (PCD) arises from mutations across more than 52 identified genes, producing defective motile cilia that cripple mucociliary clearance, disrupt organ laterality, and impair fertility. The sheer genetic heterogeneity makes one-size-fits-all drug development untenable. The review systematically maps the human preclinical modeling landscape, evaluating air-liquid interface cultures of primary airway epithelial cells, induced pluripotent stem cell (iPSC) platforms, three-dimensional organoids, spheroids, and lung-on-a-chip systems. It highlights key strategies to expand the proliferative lifespan of patient-derived cells — including BMI-1 or hTERT transduction and conditional reprogramming via ROCK inhibitor protocols — and examines CRISPR-edited isogenic models as precision tools for isolating variant-specific effects. Targeted genetic therapies assessed include small molecules, antisense oligonucleotides, mRNA replacement, and gene editing.
This review arrives at a meaningful inflection point. The cystic fibrosis field offers an instructive parallel: modulator therapies emerged only after robust cellular models enabled high-throughput screening of patient-specific variants. PCD faces a harder problem — CF is largely a single-gene disorder, while PCD encompasses dozens of causal genes and hundreds of patient-specific variants, demanding far more modular and scalable platforms. The iPSC approach holds particular promise because it theoretically allows unlimited cell expansion and genotype-matched controls, yet differentiation fidelity and ciliogenesis efficiency remain active technical hurdles. Lung-on-a-chip systems add physiological airflow dynamics but currently lack the throughput needed for broad drug screening. The field's most critical unresolved question — which airway cell types require therapeutic correction and at which differentiation stage — underscores that this is foundational groundwork, not near-term clinical translation. Incremental but strategically important.