Primary Ciliary Dyskinesia

Overview

Primary ciliary dyskinesia (PCD) is a rare inherited disorder in which tiny moving, hair-like structures called motile cilia do not form or beat normally. These cilia normally move mucus, fluid, and cells in the airways and other organs; their failure causes lifelong nasal congestion, wet cough, recurrent chest and sinus infections, ear disease, and often bronchiectasis, meaning permanently widened and damaged airways. PCD is genetically diverse, with disease-causing variants now identified in more than 55 genes; some people also have organ laterality differences, fertility problems, or other effects outside the lungs. ERS/ATS diagnostic guideline PCD clinical review

Severity and long-term outlook vary substantially by genotype, infection burden, and access to specialist care, but progressive lung damage can occur from childhood onward and can lead to severe bronchiectasis and respiratory impairment in adulthood. There is currently no approved therapy that corrects the underlying ciliary defect. Standard care is therefore preventive and supportive: regular airway-clearance physiotherapy and exercise, surveillance cultures and lung-function monitoring, prompt culture-guided antibiotics for exacerbations, and ear, nose, fertility, and other multidisciplinary care when needed. PCD Foundation consensus recommendations PCD clinical review

Scope of Recent Research (2020–present)

PCD research has shifted from describing genes and supportive treatment toward genotype-specific medicines intended to restore ciliary protein production and mucociliary clearance, the airway’s mucus-removal system. The field remains small relative to cystic fibrosis because PCD is rare and genetically heterogeneous, but it has reached an important threshold: inhaled messenger RNA (mRNA) replacement for DNAI1-related PCD has entered human studies, while mRNA replacement for CCDC40-related PCD has produced corrective results in patient cells and zebrafish. These advances are meaningful but do not yet amount to a cure; durable clinical benefit, repeated-dose safety, and applicability beyond individual genetic subtypes remain unproven. Inhaled DNAI1 mRNA therapy CCDC40 mRNA therapy

Major Breakthroughs and Emerging Therapies

The leading curative strategy is inhaled mRNA replacement. Rather than permanently changing DNA, this approach delivers a temporary RNA instruction that enables airway cells to make a missing ciliary protein. In 2022, aerosolized lipid nanoparticles carrying optimized human DNAI1 mRNA produced DNAI1 protein in multiciliated airway cells in mice and increased ciliary beat frequency in a PCD disease model. DNAI1 mRNA in mouse models DNAI1 is an attractive first target because it is a relatively recurrent PCD gene and because a full-length replacement mRNA can fit inside a lipid nanoparticle. Gene therapeutics review

This platform advanced substantially in 2025. ReCode Therapeutics reported that its selective-organ-targeting lipid nanoparticle formulation delivered DNAI1 mRNA to the airway after aerosol administration; in nonhuman primates, newly translated human DNAI1 protein was detectable in cilia, while disease-model experiments restored ciliary activity. Inhaled DNAI1 mRNA therapy Independently, investigators at the University of North Carolina and ReCode found that DNAI1 mRNA nanoparticles restored DNAI1 protein incorporation into cilia and normal ciliary beat frequency in cultured airway cells from a Dnai1-knockout mouse model, with rescued beating persisting for more than three weeks in culture. DNAI1 mRNA rescue in mouse airway cells

A second major preclinical advance is CCDC40 mRNA replacement, which is important because CCDC40-related PCD is often associated with comparatively severe lung disease. In 2026, a collaboration among University Children’s Hospital Münster, Ethris, and Portuguese academic groups treated air–liquid-interface cultures made from nasal cells of five people with CCDC40-related PCD. The lipid-nanoparticle CCDC40 mRNA treatment produced protein expression in a subset of ciliated cells, improved ciliary structure and beat frequency, improved particle transport, and increased ciliary motion and directional flow in CCDC40-deficient zebrafish. The authors stated that a Phase 1 human study is planned. CCDC40 mRNA therapy

Gene replacement, gene editing, and cell-based repair remain earlier-stage possibilities rather than current clinical options. Reviews identify viral gene delivery, CRISPR-based editing, corrected induced pluripotent stem cells, and airway basal-cell transplantation as potential ways to provide longer-lasting correction, but each must solve the problem of safely reaching enough multiciliated airway cells and restoring a complex ciliary structure assembled from many proteins. No gene-editing or cell-therapy cure for PCD has entered clinical testing. Gene therapeutics review Current and future PCD treatments

Small-molecule and inhaled therapies are also being tested, but these aim to improve mucus hydration and lung health rather than repair the causative mutation. In the multinational CLEAN-PCD Phase 2 trial, nebulized idrevloride, an epithelial sodium channel blocker, combined with hypertonic saline produced a modest short-term improvement in lung function compared with hypertonic saline alone; it did not restore ciliary function and should be considered symptomatic disease modification, not a cure. CLEAN-PCD trial

Clinical Trials and Experimental Approaches

The most consequential root-cause clinical program is RCT1100, an inhaled DNAI1 mRNA medicine sponsored by ReCode Therapeutics for adults with DNAI1-related PCD. The first-in-human Phase 1 study, RCT1100-101, began on February 18, 2023, completed primary data collection on July 25, 2024, and completed on January 13, 2025; it evaluated a single ascending nebulized dose in healthy volunteers and adults with DNAI1-related PCD. RCT1100-101 trial record A subsequent Phase 1 study, RCT1100-102, evaluated safety, tolerability, ciliary rescue, and pharmacodynamic effects in adults with PCD and is listed as completed. RCT1100-102 trial record

ReCode’s ongoing/open-label Phase 1b RCT1100-103 study evaluates repeated dosing and mucociliary clearance in adults with DNAI1-related PCD. RCT1100-103 trial record At the American Thoracic Society meeting in May 2026, the company reported preliminary results from this program: 57% of participants in RCT1100-103 achieved what it described as a meaningful improvement in mucociliary clearance at 12 weeks, and earlier studies reportedly found no serious or Grade 3-or-higher treatment-emergent adverse events at tested doses. These are encouraging early company-reported findings rather than peer-reviewed evidence of durable clinical benefit or cure. ReCode ATS 2026 update

Several non-curative trials have nevertheless strengthened PCD care. The Phase 2 CLEAN-PCD trial tested idrevloride with and without hypertonic saline across 32 specialist centers and found a 1.5 percentage-point advantage in percent-predicted FEV1 after 28 days for the idrevloride-plus-hypertonic-saline combination versus hypertonic saline alone. CLEAN-PCD trial abstract In the investigator-led BESTCILIA Phase 3 trial, three-times-weekly azithromycin for six months reduced the respiratory-exacerbation rate by about 55% versus placebo in 90 participants, but it addressed infection burden rather than the underlying ciliary defect. BESTCILIA Phase 3 trial

Methodologies and Scientific Approaches

Researchers increasingly use patient-derived airway epithelial cells grown at an air–liquid interface, which allows cells from nasal brushings to develop motile cilia in the laboratory. These models can measure whether a therapy restores the correct ciliary protein, ciliary ultrastructure, beat frequency, beat pattern, and movement of fluorescent particles that model mucus transport. CCDC40 mRNA therapy DNAI1 programs also use mouse knockout airway cultures, aerosol dosing in mice and nonhuman primates, and protein-localization studies to establish whether inhaled nanoparticles reach the intended ciliated cells. Inhaled DNAI1 mRNA therapy DNAI1 mRNA rescue in mouse airway cells

Clinical development is beginning to use mucociliary clearance as a pharmacodynamic biomarker: it asks whether treatment measurably improves airway mucus movement before larger trials test outcomes such as exacerbations, lung-function trajectory, imaging changes, and quality of life. Genetic diagnosis is equally central, because current mRNA candidates only apply to people whose PCD is caused by mutations in the specific gene being replaced. RCT1100-103 trial record ERS/ATS diagnostic guideline

Leading Institutions and Funding

ReCode Therapeutics is the first company to bring a PCD-directed genetic medicine into human trials through its RCT1100 DNAI1 mRNA program. RCT1100-101 trial record Key preclinical contributors include the University of North Carolina’s Marsico Lung Institute and collaborators at ReCode for DNAI1 delivery studies, as well as University Children’s Hospital Münster, Ethris, NOVA Medical School, and University of Lisbon groups for CCDC40 mRNA research. DNAI1 mRNA rescue in mouse airway cells CCDC40 mRNA therapy

Academic and patient-led networks remain essential because no single center sees enough people with each PCD genotype to run definitive trials alone. The PCD Foundation supports a clinical and research-center network and has issued proposals for a clinical-trials network intended to support observational, translational, and interventional research. PCD Foundation clinical centers PCD Foundation clinical-trials network RFA As one representative federal investment, the National Heart, Lung, and Blood Institute awarded Northwestern University $741,404 in fiscal year 2025 and $726,576 in fiscal year 2026 for a project to identify and characterize additional PCD-causative genes, for a reported total of $1,467,980 through April 2026. NIH/NHLBI award R01HL173147

Strengths, Limitations, and Challenges

The strongest recent evidence is that inhaled lipid-nanoparticle mRNA can restore a missing ciliary protein and improve ciliary motion in relevant laboratory models, and that DNAI1 mRNA delivery has now produced preliminary evidence of biological activity in people. Inhaled DNAI1 mRNA therapy ReCode ATS 2026 update The non-viral, inhaled approach is potentially repeat-dose compatible and avoids permanent genome modification, while genotype-specific programs offer a direct way to correct the absent protein rather than only manage consequences. Gene therapeutics review

The central limitation is that PCD is not one disease at the molecular level: more than 55 genes can cause it, so DNAI1 or CCDC40 replacement will only help the subset with variants in those genes. ERS/ATS diagnostic guideline mRNA treatment is also temporary, so patients may need chronic repeat inhalation; researchers must establish dosing frequency, immune and inflammatory safety, delivery to enough airway regions, and whether improved mucociliary clearance prevents bronchiectasis progression over years. DNAI1 mRNA rescue in mouse airway cells In addition, an inhaled airway treatment would not necessarily correct fertility, laterality, or other non-pulmonary manifestations—an inference based on the localized route of delivery and the multisystem nature of PCD. PCD clinical review Inhaled DNAI1 mRNA therapy

Outlook and Future Directions

As of August 8, 2026, PCD is closer to a root-cause treatment than it was in 2020, but not close to a broadly applicable cure. The next milestones are peer-reviewed full results from repeated-dose RCT1100 studies; confirmation that improved mucociliary clearance translates into fewer infections, preserved lung function, and better quality of life; expansion from DNAI1 to additional genotypes such as CCDC40; and evidence that repeated inhaled mRNA is safe and practical over years. If these milestones succeed, PCD care could move from managing mucus and infections toward gene-specific restoration of ciliary function, initially for selected genetic subtypes rather than the entire PCD population. RCT1100-103 trial record CCDC40 mRNA therapy

References

• ERS/ATS diagnostic guideline — European Respiratory Society and American Thoracic Society, 2025.
• PCD clinical review — American Academy of Pediatrics, 2024.
• PCD Foundation consensus recommendations — Shapiro et al., 2016.
• Inhaled DNAI1 mRNA therapy — Hennig et al., 2025.
• CCDC40 mRNA therapy — Wohlgemuth et al., 2026.
• DNAI1 mRNA in mouse models — Woo et al., 2022.
• Gene therapeutics review — Keiser et al., 2023.
• DNAI1 mRNA rescue in mouse airway cells — Smith et al., 2025.
• Current and future PCD treatments — Werner et al., 2021.
• CLEAN-PCD trial — Ringshausen et al., 2023.
• RCT1100-101 trial record — ClinicalTrials.gov, 2026.
• RCT1100-102 trial record — ClinicalTrials.gov, 2026.
• RCT1100-103 trial record — ClinicalTrials.gov, 2026.
• ReCode ATS 2026 update — ReCode Therapeutics, 2026.
• CLEAN-PCD trial abstract — European Respiratory Society, 2023.
• BESTCILIA Phase 3 trial — Kobbernagel et al., 2020.
• PCD Foundation clinical centers — PCD Foundation, 2026.
• PCD Foundation clinical-trials network RFA — PCD Foundation, 2025.
• NIH/NHLBI award R01HL173147 — U.S. Department of Health and Human Services, 2026.