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Primary Ciliary Dyskinesia

Recent research efforts aimed at curing Primary Ciliary Dyskinesia.

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Primary Ciliary Dyskinesia

Overview

Primary ciliary dyskinesia (PCD) is a rare inherited disorder in which microscopic, hair-like structures called motile cilia do not move normally or are missing key structural parts. In the airways, cilia normally sweep mucus, germs, and debris out of the lungs; when that system fails, people can develop chronic wet cough, recurrent sinus and ear infections, bronchiectasis (permanent widening and damage of airways), and progressive lung disease. Some people also have organs arranged differently in the chest or abdomen, fertility problems, or symptoms beginning with breathing distress soon after birth. PCD is genetically diverse: at least 54 disease-causing genes have been identified. Clinical review (pubmed.ncbi.nlm.nih.gov)

Outcomes vary widely, but lung function declines on average from school age into adulthood, even in specialist care, while some individuals remain stable or improve. Current care is therefore preventive and supportive rather than curative: regular airway-clearance physiotherapy, exercise, prompt culture-guided treatment of infections, management of sinus and ear disease, vaccination, and monitoring of lung structure and function. For people with frequent exacerbations, long-term azithromycin can reduce exacerbation frequency, but it does not repair the ciliary defect. Longitudinal lung-function study BESTCILIA phase 3 trial (pubmed.ncbi.nlm.nih.gov)

Scope of Recent Research (2020–present)

Research activity has accelerated from improving symptom control and trial infrastructure toward treatments that address the genetic cause of PCD. The dominant questions are how to deliver a therapy into the correct airway cells, how long restored ciliary function lasts, which genes and variants are practical first targets, and which measurements best show a meaningful clinical benefit. The field is still early: the first inhaled genetic medicine has produced preliminary human biological-activity data, but no therapy has yet demonstrated that it can durably halt or reverse PCD lung disease. Gene-therapy review RCT1100 phase 1b abstract (pubmed.ncbi.nlm.nih.gov)

Major Breakthroughs and Emerging Therapies

The clearest advance is inhaled messenger RNA (mRNA) replacement for PCD caused by pathogenic variants in DNAI1, a gene that encodes a component of the motor machinery enabling cilia to beat. ReCode Therapeutics’ RCT1100 packages normal DNAI1 mRNA in selective organ-targeting lipid nanoparticles and delivers it by nebulizer. In human airway-cell models, the treatment led to production and ciliary incorporation of DNAI1 protein and restored ciliary motion; aerosol dosing in non-human primates also produced DNAI1 protein in relevant airway cell types. These results matter because mRNA replacement does not need to permanently alter a patient’s DNA and may be adaptable to other PCD genes, although it would need repeat dosing. DNAI1 mRNA preclinical study (pmc.ncbi.nlm.nih.gov)

A related mouse-cell study independently supported this strategy: lipid-nanoparticle delivery of mouse or human DNAI1 mRNA into airway cultures from conditional Dnai1 knockout mice produced protein in ciliary axonemes and substantially rescued ciliary activity. Together, these studies establish a plausible platform for gene-specific replacement therapies, but they remain preclinical evidence rather than proof of a durable clinical cure. Dnai1 mouse-cell rescue study (pubmed.ncbi.nlm.nih.gov)

Genome editing has also moved from theory to patient-cell proof of concept. In 2026, investigators used an adenosine base editor—an engineered enzyme that can change one DNA letter without making a full double-strand DNA break—delivered by adeno-associated virus (AAV) to correct a shared RSPH4A variant in cells from two people with PCD. In cells from one participant, editing reached about 20% and the proportion of normally moving cilia increased by about 30 percentage points. However, limited AAV penetration into deeper cell layers constrained effectiveness, and this remains laboratory-stage work with substantial delivery, durability, and safety questions before human testing. RSPH4A base-editing proof of concept (pubmed.ncbi.nlm.nih.gov)

Small-molecule and mucus-hydration approaches are not cures, but they may reduce harm while genetic therapies mature. In the CLEAN-PCD study, the inhaled epithelial sodium-channel blocker idrevloride plus hypertonic saline modestly improved lung function over 28 days compared with hypertonic saline alone; idrevloride alone did not show a significant comparison with placebo. This approach targets airway-surface hydration and mucus clearance rather than restoring ciliary structure or correcting a mutation. CLEAN-PCD phase 2 trial (pubmed.ncbi.nlm.nih.gov)

Clinical Trials and Experimental Approaches

RCT1100 is the most important disease-modifying clinical program to date. In the open-label, multiple-dose phase 1b RCT1100-103 study, 14 adults with DNAI1-related PCD inhaled 5 mg three times weekly for 12 weeks. At week 12, three participants had at least a 5-percentage-point absolute improvement in measured whole-lung mucociliary clearance and eight had an improvement of at least 2 percentage points; lung function by FEV1 was unchanged. All participants reported mild or moderate adverse events, with no serious or grade 3 or higher treatment-related events reported. These are encouraging biological signals, but the study was small, uncontrolled, and reported as a conference abstract, so it cannot establish efficacy or a cure. RCT1100-103 phase 1b results RCT1100-103 registry record (doi.org)

Earlier RCT1100 studies provide preliminary safety information. The single-dose phase 1a RCT1100-101 enrolled nine adults, and the multiple-dose phase 1b RCT1100-102 enrolled seven adults; neither reported serious adverse events or grade 3 or higher adverse events. In the small bronchoscopy study, however, investigators reported no clear difference in average outer dynein-arm number, ciliary movement, or DNAI1 staining after treatment, underscoring that the human pharmacodynamic evidence remains mixed and preliminary. RCT1100-101 and -102 safety abstract (academic.oup.com)

Other notable completed trials have focused on disease management rather than correction. BESTCILIA, a multinational phase 3 trial, found that azithromycin taken three times weekly for six months reduced respiratory exacerbations by about 55% relative to placebo. CLEAN-PCD tested idrevloride with or without hypertonic saline in a phase 2 crossover design. These trials demonstrate that PCD can support multinational interventional research, but neither treatment corrects the underlying genetic defect. BESTCILIA phase 3 trial CLEAN-PCD phase 2 trial (pubmed.ncbi.nlm.nih.gov)

Methodologies and Scientific Approaches

Researchers increasingly use patient-derived airway epithelial cells grown at an air–liquid interface, where cells differentiate into mucus-producing and ciliated airway tissue, to test whether a treatment restores beat pattern, beat frequency, and mucociliary transport. Nasal-brushing-derived airway organoids can preserve patient-specific defects and have been used both to characterize PCD mutations and to demonstrate repair of a patient-specific mutation with genetic editing tools. Patient-derived airway-organoid model (pubmed.ncbi.nlm.nih.gov)

Additional platforms include induced pluripotent stem cell-derived airway epithelium, disease-model mice, and advanced imaging. These systems combine high-speed video microscopy, transmission electron microscopy, immunofluorescence for ciliary proteins, digital PCR for editing rates, and functional readouts such as mucociliary clearance. In clinical trials, aerosol-based radionuclide measurements of mucociliary clearance are becoming particularly important because conventional FEV1 may be variable and insensitive to early biological effects in PCD. hiPSC airway model PCD lung-function variability study (pubmed.ncbi.nlm.nih.gov)

Leading Institutions and Funding

ReCode Therapeutics is leading the first clinical mRNA-replacement program, working with specialist PCD centers in the United States, United Kingdom, Denmark, and Germany. Key academic contributors include the University of North Carolina at Chapel Hill, University Hospital Münster, Copenhagen University Hospital–Rigshospitalet, Royal Brompton Hospital, the University of Pisa and Pisa University Hospital, and the University of Siena. The European PCD Clinical Trial Network provides a framework for coordinated multinational studies, while the PCD Foundation’s Clinical and Research Centers Network and American Thoracic Society partnership support North American trial readiness and young-investigator funding. PCD Clinical Trial Network PCD Foundation research network (pubmed.ncbi.nlm.nih.gov)

Public and charitable investment has built much of the necessary infrastructure. The European Commission’s BESTCILIA program, coordinated by the University of Münster, had a reported EU contribution of approximately €3.0 million and supported registries, outcome measures, diagnostic work, and randomized trials. A 2024 international survey nevertheless found that researchers viewed PCD funding as harder to obtain than funding for other diseases, with low awareness, competition, limited commercial incentives, and disease rarity as major barriers. BESTCILIA European Commission record PCD research-priorities survey (cordis.europa.eu)

Strengths, Limitations, and Challenges

PCD research now has a credible path from patient-derived models to targeted intervention: genetic diagnoses can identify treatment-eligible groups, airway models can measure restoration of ciliary function, and RCT1100 has shown that inhaled mRNA can reach the human airway with an early signal of improved mucociliary clearance in some participants. The strongest near-term advantage of mRNA replacement is that it can supply a full normal protein without permanently editing DNA. DNAI1 mRNA preclinical study RCT1100-103 phase 1b results (pmc.ncbi.nlm.nih.gov)

The central limitations are biological and practical. PCD involves more than 50 genes, so a therapy for DNAI1 will help only a subset of patients; ciliated cells turn over, making repeated delivery or treatment of airway stem/progenitor cells important; mucus obstruction and airway anatomy may restrict delivery to the cells that need treatment; and chronic inflammation or established bronchiectasis may not be fully reversible even if ciliary function improves. Permanent editing introduces additional risks, including unintended edits and AAV-delivery limitations. Small patient populations, heterogeneous genotypes, limited funding, and uncertain trial endpoints further complicate the demonstration of long-term clinical benefit. RSPH4A base-editing proof of concept Preclinical human-models review PCD research-priorities survey (pubmed.ncbi.nlm.nih.gov)

Outlook and Future Directions

As of October 4, 2026, PCD is not close to a broadly available cure, but it has entered a new phase in which a root-cause therapy has reached human trials. The milestones to watch are controlled and longer RCT1100 studies showing durable improvements in mucociliary clearance, exacerbations, quality of life, imaging, and lung-function trajectory; confirmation that repeat inhaled dosing remains safe; expansion of mRNA replacement to additional genes; and improved editing or delivery systems that reach airway progenitor cells. A practical future is more likely to involve several gene- or variant-specific treatments than one universal cure, with earlier diagnosis and intervention offering the best chance of preventing irreversible airway damage. RCT1100-103 phase 1b results Gene-therapy review (doi.org)

References

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