RARE DISEASE
Primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia
Synonyms: PCD
Synonyms: PCD
Synonyms: PCD
Drug discovery
9
drugs
With orphan designations
Overview
Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disorder caused by defective ciliary structure/function, impairing mucociliary clearance. This leads to chronic sino-pulmonary infections, neonatal respiratory distress, bronchiectasis, and laterality defects (situs inversus in 50% of cases). Associated features include chronic otitis media, subfertility, and rare hydrocephalus. Diagnosis combines nasal nitric oxide testing, genetic analysis, and ciliary ultrastructural studies [1][5][7][12].
Burden
Progressive lung function decline, with childhood PCD showing worse outcomes than cystic fibrosis in some cohorts [4][19]
High treatment burden: Daily physiotherapy (1-2 hours) + frequent antibiotic courses [4][8]
40-50% have situs inversus; 12% develop heterotaxy with congenital heart defects [1][7][19]
Therapies
Symptomatic management: Airway clearance (physiotherapy, oscillatory devices), mucolytics, and prophylactic antibiotics [3][8]
Infection control: Aggressive treatment of pulmonary exacerbations with culture-directed antibiotics [4][8]
Emerging approaches: Gene therapy and mRNA transcript therapies targeting specific mutations (e.g., DNAI1, DNAH5) in clinical trials [18][13]
Categories: rare genetic diseases, rare infertility disorders, rare respiratory diseases
Research Papers
448 drug discovery papers about Primary ciliary dyskinesia, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
448 drug discovery papers about Primary ciliary dyskinesia, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-10 | Amiloride mitigates respiratory distress caused by WFDC2 deficiency via inhibiting the epithelial sodium channel.
Chronic airway diseases such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) pose substantial clinical challenges. Here, we explore the p.C97W variant in WAP four-disulfide core domain protein 2 (WFDC2), proposed as a new genetic origin of respiratory distress, especially among Koreans. Whole-exome and whole-genome sequencing (WES/WGS) are performed on 64 patients from 62 families presenting with severe bronchiectasis and chronic rhinosinusitis. Pathogenic variants are found in 19.4% of families, including a novel homozygous WFDC2 missense variant (c.291 C > G, p.Cys97Trp) in five unrelated families. WFDC2 is expressed in lung epithelial cells, and the p.C97W variant impairs WFDC2 protein folding, secretion, and function. Wfdc2 p.C147W knock-in mice exhibit respiratory failure due to the hyperactive epithelial sodium channel (ENaC) linked to increased PRSS8 activity and recapitulate human disease. Treatment with amiloride, an ENaC inhibitor, improves survival and respiratory function in these mice. In conclusion, the p.C97W variant in WFDC2 is a critical genetic factor in severe chronic airway disease that shares clinical features with CF and PCD. Given its implications for diagnosis and treatment, genetic testing for WFDC2 mutations in individuals with CF- or PCD-like symptoms is recommended.
2026-09-07 | Pulmonary exacerbations in primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction characterized by impaired mucociliary clearance, chronic sino-pulmonary disease, and progressive bronchiectasis. Pulmonary exacerbations (PEx) are a major contributor to morbidity, lung function decline, and healthcare utilization in PCD, yet historically have been poorly defined and understudied. This review summarizes current evidence regarding the definition, epidemiology, pathophysiology, clinical impact, and management of PEx in PCD, with emphasis on recent advances that are beginning to establish a disease-specific evidence base. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. Prospective cohort data demonstrate that PEx occur frequently across all age groups, including infancy, and are associated with impaired lung function recovery, structural lung damage, and increased disease severity, particularly in patients with chronic Pseudomonas aeruginosa infection. Emerging biomarkers such as lung clearance index and exhaled breath analysis using volatile organic compounds may improve prediction and monitoring of exacerbations. Management strategies currently rely largely on extrapolation from cystic fibrosis and non-cystic fibrosis bronchiectasis and include prompt antibiotic therapy, intensified airway clearance, and supportive care. However, recent randomized controlled trials, including BESTCILIA and CLEAN-PCD, have provided the first high-quality evidence supporting maintenance azithromycin therapy and airway hydration strategies in PCD. Despite these advances, important gaps remain regarding optimal exacerbation definitions, treatment duration, predictors of incomplete recovery, and the role of anti-inflammatory and targeted therapies. Continued international collaboration, validated outcome measures, and development of mechanism-based therapies will be essential to improve long-term outcomes for patients with PCD. • Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction causing chronic sino-pulmonary disease, recurrent respiratory infections, and progressive bronchiectasis from early childhood. • Pulmonary exacerbations (PEx) are a major driver of morbidity and lung function decline in PCD, but have historically been inconsistently defined and understudied, with management largely extrapolated from cystic fibrosis and non-CF bronchiectasis. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. • Prospective international cohort data (Schreck et al. 2026) establish a PEx incidence of approximately 3.1 per person per year across all age groups, with higher risk in adult females and Pseudomonas aeruginosa-colonized patients. PEx are frequent even in the first 2 years of life. Pulmonary exacerbations cause substantial acute loss in forced expiratory volume in 1 s (FEV1), and approximately 20-25% of events do not recover to baseline lung function. • The BESTCILIA trial provides the first high-quality evidence that maintenance azithromycin reduces PEx frequency by 55% in PCD, and the CLEAN-PCD trial provides proof-of-concept for airway rehydration (ENaC blockade + hypertonic saline) as a PCD-specific therapeutic strategy.Novel anti-inflammatory therapies (DPP1 inhibitors, neutrophil elastase inhibitors), inhaled biologics, and gene-directed strategies are entering the PCD therapeutic pipeline and may transform future PEx prevention.
2026-08-22 | Evaluating the efficacy and safety of macrolide therapy in primary ciliary dyskinesia: A systematic review.
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired ciliary function, defective mucociliary clearance, recurrent respiratory infections, and progressive respiratory morbidity. Macrolides, particularly azithromycin, have antibacterial, anti-inflammatory, and immunomodulatory properties and may therefore provide therapeutic benefit in PCD. This systematic review evaluated the efficacy and safety of macrolide therapy in patients with PCD. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and was prospectively registered in International Prospective Register of Systematic Reviews (CRD42024553793). PubMed, Scopus, Web of Science, Embase, Cochrane, and Google Scholar were searched for studies published from January 1, 1990, to June 18, 2024. Eligibility criteria were defined using the population, intervention, comparator, outcomes, and study design framework. Study selection, data extraction, and risk of bias assessment were performed independently by 3 reviewers. A meta-analysis was not performed because of substantial methodological heterogeneity across the included studies. Of 765 records identified, 9 studies met the inclusion criteria. These included 2 in vitro studies and 7 clinical studies, comprising case reports, case series, retrospective observational studies, and 1 randomized, placebo-controlled phase 3 trial. Across the clinical studies, sample sizes ranged from 1 to 90 participants. Overall, the available evidence suggested that macrolide therapy, particularly azithromycin, may reduce respiratory exacerbations and improve selected clinical symptoms in patients with PCD. Mechanistic in vitro evidence further indicated that azithromycin may reduce pro-inflammatory cytokine production and promote epithelial barrier repair. However, the included studies varied considerably in design, population characteristics, treatment protocols, and outcome definitions. Macrolides, especially azithromycin, may have a beneficial role in the management of PCD by reducing respiratory exacerbations, improving selected symptoms, and modulating airway inflammation. Nevertheless, the certainty of evidence remains limited by methodological heterogeneity, small sample sizes, and the scarcity of randomized controlled trials. Further large-scale, well-designed, PCD-specific clinical studies are required to confirm these preliminary findings and establish standardized treatment protocols.
2026-08-18 | Clinical features, misdiagnosis, and treatment of clinically diagnosed complete Kartagener syndrome: A three-case series for primary care.
Kartagener syndrome (KS) is a rare autosomal recessive motile ciliopathy and a well-recognized subtype of primary ciliary dyskinesia, classically defined by the triad of situs inversus totalis, chronic sinusitis, and bronchiectasis, with frequent accompanying infertility. Because of its non-specific clinical manifestations overlapping with common respiratory disorders and limited availability of gold-standard diagnostic tools in primary care settings, KS is frequently misdiagnosed or diagnosed late. This study retrospectively analyzed the clinical data, diagnostic trajectories, and treatment outcomes of three adult patients with clinically diagnosed complete KS admitted to our institution between May 2021 and December 2022. All patients presented with long-standing recurrent cough and expectoration; two presented with hemoptysis and one with type II respiratory failure. Initial misdiagnoses included bronchiectasis, non-tuberculous mycobacterial infection, and chronic obstructive pulmonary disease. Clinical diagnosis of complete KS was established based on the classic triad on imaging combined with core clinical features, as confirmatory genetic or ultrastructural testing was not available. Pathogen testing detected Acinetobacter baumannii in one patient, while another patient had a coinfection of Pseudomonas aeruginosa and Enterobacter cloacae. One more patient received empirical antimicrobial therapy because their family declined bronchoscopy. After individualized treatment, clinical improvement was observed in all patients, with symptom resolution, normalized inflammatory markers, and stable disease during 6-12 months of follow-up. These findings underscore that the combined features of "situs inversus totalis + bronchiectasis + chronic sinusitis + childlessness/infertility (when formally confirmed)" are key diagnostic clues for KS in primary care. Primary care clinicians should strengthen awareness of this rare entity and use a multisystem diagnostic approach to prevent misdiagnosis and underdiagnosis. Prompt targeted antimicrobial therapy and sustained comprehensive long-term management were associated with favorable clinical outcomes in this small case series.
2026-06-01 | High-dose continuous infusion of piperacillin/tazobactam via elastomeric pump in a pediatric patient with Kartagener syndrome: pharmacokinetic target attainment and clinical outcome.
Multidrug-resistant Achromobacter xylosoxidans infections in pediatric patients with primary ciliary dyskinesia (PCD) often require prolonged intravenous therapy. We evaluated the pharmacokinetics of continuous infusion piperacillin/tazobactam (16 g/2 g daily) in a 13-year-old male with situs inversus and chronic otitis media transitioned from hospital-based electronic infusion to home-based Outpatient Parenteral Antimicrobial Therapy (OPAT) using elastomeric pumps. Plasma concentrations were measured by Therapeutic Drug Monitoring (TDM), and tissue exposure was estimated using conservative penetration coefficients. Drug concentrations consistently remained above the MIC (≤2 mg/L). During hospitalization, steady-state concentrations were stable (27.2-29.0 mg/L; CV 4.5%), whereas during OPAT they were higher and more variable (53.9-80.1 mg/L; CV 20.1%), consistent with the known non-linear delivery profiles of elastomeric devices. Despite this variability, TDM confirmed sustained supratherapeutic exposure, with estimated tissue concentrations remaining >5-fold above the MIC. Clinical resolution was achieved without adverse events, supporting the role of TDM-guided OPAT in difficult-to-treat infections.
cell therapies
2026-03-30 | [Normal Delivery by Intracytoplasmic Sperm Injection with Epididymal Sperm in a Patient with Azoospermia and Kartagener Syndrome].
Kartagener syndrome is defined as a primary ciliary dyskinesia with visceral inversion, bronchiectasis, and chronic sinusitis. Male patients with primary ciliary dyskinesia including Kartagener syndrome are also associated with male infertility, mainly because of sperm tail immobility. We report a case in a 36-year-old man with Kartagener syndrome and azoospermia. An examination indicated obstructive azoospermia. Therefore, testicular sperm extraction and microsurgical epididymal sperm aspiration were performed, and sperm retrieval was successful. Motile epididymal spermatozoa were used for the first intracytoplasmic sperm injection, and a single embryo was transferred. The course of pregnancy was uneventful and a healthy boy was delivered. Intracytoplasmic sperm injection following microsurgical epididymal sperm aspiration is an effective treatment for infertility due to Kartagener syndrome.
2026-03-21 | Deuterosomal cells are the responsible lineage for multiciliogenesis in human airway differentiation.
Multiciliated cells (MCCs) are pivotal in airway defense via their motile cilia to eliminate inhaled pathogens and particles. Genetic variants in primary ciliary dyskinesia (PCD) disrupt ciliary function, resulting in chronic respiratory infections. The formation of MCCs requires centriole amplification mediated by non-membranous organelles called deuterosomes, whose regulatory mechanisms remain poorly characterized in humans. Single-cell transcriptomic analyses have identified "deuterosomal cells" (DCs), a transient cell population that emerges during multiciliogenesis. DCs are challenging to investigate owing to their scarcity. To elucidate the role of DCs, iPSC-derived airway epithelial cells were used to identify CD36 as a specific surface marker. Furthermore, iPSCs were established from a patient with PCD harboring Cyclin O (CCNO) variants, along with gene-corrected controls. Patient-derived iPSCs demonstrated defective MCC differentiation and aberrant DCs attributed to CCNO deficiency. This study provides a human iPSC-based platform for investigating the mechanisms underlying airway multiciliogenesis and PCD modeling.
2025-04-01 | Combined cellular and gene therapy to treat primary ciliary dyskinesia
Primary Ciliary Dyskinesia (PCD) is a genetic disease caused by mutations that alter cilia beating, including in the respiratory airways. This results in poor mucus clearance, severe morbidity, and increased mortality. We hypothesized that bronchial cilia beating can be restored using genetically corrected iPSC differentiated into air - liquid interface bronchial epithelium model (iALI) for autologous cell therapy. We have previously demonstrated that corrected cells derived from a PCD patient iPS line can be differentiated into iALI with functional ciliary beating. The current aim of the project is to evaluate the engraftment potential of these corrected cells and their ability to repair the pathological model post-engraftment. Several key issues need to be addressed identifying competent cells for bronchial engraftment, exploring various strategies to pre-treat the bronchial epithelium, and assessing the recovery of the ciliary beating recovery to assure bronchial repair. Our team has established the differentiation of iPSCs into iALI. We have generated a PCD patient iPSC line using Sendai viruses, a corresponding CRISPR/Cas9 corrected cell line, as well a wild-type iPSC line and its CRISPR/Cas9 mutated counterpart. We also generated a GFP-iPSC line that expresses the fluorescent GFP protein under the human elongation factor 1 alpha promoter (EF1a), which allows us to track the engraftment of GFP-labeled bronchial stem cells in both control and mutated iALI models. Our results suggest that lung progenitors at the ventralized anterior foregut endoderm stage could be the most efficient cells for engraftment. Their self-renewal capability and ability to differentiate into various cell types of the bronchial epithelium are promising for developing a long-term and effective therapy. Regarding bronchial erosion, we found that promoting cell engraftment is crucial due to the barrier function of the intact bronchial epithelium and the lack of selective advantage of corrected cells. Various chemical and enzymatic strategies have shown potential, but their safety for in-vivo use needs further assessment. Furthermore, GFP-expressing engrafted cells displaying cilia suggest successful differentiation into ciliated cells, though functional recovery still requires confirmation. In conclusion, the engraftment of corrected lung progenitors into eroded bronchial epithelium appears to be a promising therapeutic strategy to PCD. Next step of the project involves developing this therapy for in-vivo application, assessing its safety and efficacy in an immunodeficient mini-pig model.
2024-11-28 | Targeted pre-conditioning and cell transplantation in the murine lower respiratory tract.
Transplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary- and pluripotent stem cell (PSC)-derived basal cells to efficiently engrai into the mouse trachea aier injury. However, there are many hurdles to overcome in translating these approaches to humans including developing safe and efficient methods for delivery in larger animal models. We propose a model which targets preconditioning and cell-delivery to the intrapulmonary airways utilizing a micro- bronchoscope for delivery. The detergent polidocanol was adapted for distal lung pre-conditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24-hours post-delivery. While initial re- epithelialization of airways occurred later than tracheas, complete repair was observed within 7-days. Both PSC-derived and primary basal cells delivered via micro-bronchoscope post-polidocanol injury engraied in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted pre-conditioning and cell delivery to the conducting intra- pulmonary airways, providing an important framework for pre-clinical translation of approaches for engineered airway epithelial regeneration.
2024-11-06 | Life-long functional regeneration of in vivo airway epithelium by the engraftment of airway basal stem cells.
Durable and functional regeneration of the airway epithelium in vivo with transplanted stem cells has the potential to reconstitute healthy tissue in diseased airways, such as in cystic fibrosis or primary ciliary dyskinesia. Here, we present detailed protocols for the preparation and culture expansion of murine primary and induced pluripotent stem cell-derived airway basal stem cells (iBCs) and methods for their intra-airway transplantation into polidocanol-conditioned murine recipients to achieve durable in vivo airway regeneration. Reconstitution of the airway tissue resident epithelial stem cell compartment of immunocompetent mice with syngeneic donor cells leverages the extensive self-renewal and multipotent differentiation properties of basal stem cells (BCs) to durably generate a broad diversity of mature airway epithelial lineages in vivo. Engrafted donor-derived cells re-establish planar cell polarity as well as functional ciliary transport. By using this same approach, human primary BCs or iBCs transplanted into NOD-SCID gamma recipient mice similarly display engraftment and multilineage airway epithelial differentiation in vivo. The time to generate mouse or human iBCs takes ~60 d, which can be reduced to ~20 d if previously differentiated cells are thawed from cryopreserved iBC archives. The tracheal conditioning regimen and cell transplantation procedure is completed in 1 d. A competent graduate student or postdoctoral trainee should be able to perform the procedures listed in this protocol.
proteins
2026-09-23 | Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.
Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with an HTX/laterality defect spectrum, presenting with complex CHD without extracardiac organ malposition and no evidence of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1 G > A, chr2:227,903,110 G > A (GRCh38)) and a paternally inherited missense variant (c.341 G > A; p.Arg114Gln, chr2: 227,893,818 G > A (GRCh38)), both classified as variants of uncertain significance under ACMG/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1 G > A as likely pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.
2026-09-07 | Clinical Outcomes of Chronic Airway Infection in Primary Ciliary Dyskinesia.
Primary ciliary dyskinesia (PCD) is a rare disorder of impaired respiratory mucociliary clearance and chronic pulmonary infections. The clinical impact of chronic infection is poorly understood. The objective of this single-center, retrospective cohort study was to assess clinical outcomes of people with PCD and chronic airway infection. We hypothesized that chronic airway infection would be associated with greater declines in lung function and higher pulmonary exacerbation rates. Linear mixed effects models were used to analyze the association of chronic infection with percent predicted forced expiratory volume in 1 s (ppFEV1). Poisson mixed models were used to analyze the association of chronic infection with exacerbation rates. Thirty-two people with PCD were included: 19 (59%) with chronic infection including 5 (16%) with chronic Pseudomonas aeruginosa (PA), 10 (31%) with chronic Haemophilus influenzae (HI), 2 (6%) with chronic methicillin-sensitive Staphylococcus aureus (MSSA) and 2 (6%) with chronic Aspergillus fumigatus (AF). A lower ppFEV1 was associated with chronic AF, but not with other chronic infections. The exacerbation rate ratio was 1.29 [95% CI 0.72, 2.30] (p = 0.388), 5.03 [95% CI 1.41, 18.0] (p = 0.013), 0.41 [95% CI 0.16, 1.08] (p = 0.072) and 2.19 [95% CI 0.39, 12.30] (p = 0.373) after development of chronic HI infection, chronic PA infection, chronic MSSA infection and chronic AF infection, respectively. In this single-center, retrospective study of chronic airway infections in PCD, chronic infection with PA was associated with a greater rate of pulmonary exacerbations but ppFEV1 decline was only associated with chronic AF infection.
2026-07-22 | Biallelic RSPH4A loss-of-function variants cause primary ciliary dyskinesia in a Chinese patient.
Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by defective motile cilia function, affecting approximately one in 7,500 to one in 10,000 live births. Pathogenic variants in radial spoke head genes, including RSPH4A, cause PCD with distinctive central-microtubular-pair defects. However, the functional consequences of novel RSPH4A variants remain poorly characterized, limiting genetic counseling and prenatal diagnostic capabilities. This study aims to reveal the genetic etiology of PCD in an affected family and the clinical significance of the two novel RSPH4A variants identified in this PCD-affected pedigree. We recruited a five-member Chinese family including an 11-year-old female PCD proband presenting with chronic bronchiectasis and recurrent respiratory infections. Comprehensive clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed to identify genetic variants. Bioinformatics analyses including protein sequence alignment and structural modeling were conducted. Experimental validation employed site-directed mutagenesis, quantitative real-time PCR, and Western blotting in HEK293T cells to characterize variant effects on mRNA stability and protein expression. WES identified compound heterozygous RSPH4A variants in the proband: RSPH4A (NM_001010892.3): c.2T>C (p.Met1Thr) inherited from the mother and RSPH4A (NM_001010892.3): c.854delA (p.Lys286Serfs*22) inherited from the father, showing strict co-segregation with the disease phenotype. The c.2T>C variant disrupted the translation initiation codon, while c.854delA introduced a premature termination codon within the radial spoke head domain. Cross-species analysis demonstrated high conservation of the affected region across 15 vertebrate species. Structural modeling predicted complete loss of the radial spoke head domain in the truncated protein. Functional studies revealed that c.2T>C severely impaired protein translation despite intact mRNA levels, whereas c.854delA triggered nonsense-mediated mRNA decay and produced unstable truncated protein. Both variants resulted in substantial reduction in functional RSPH4A protein expression. This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies. These findings offer compelling proof in favor of a molecular diagnosis of PCD in this family and enable carrier screening for at-risk relatives. The experimental validation strategy establishes a framework for interpreting variants of uncertain significance in PCD genes, facilitating accurate prenatal diagnosis and preimplantation genetic testing to reduce the recurrence risk and birth defect incidence in PCD. Furthermore, understanding the precise functional consequences of RSPH4A variants informs genotype-phenotype correlations and may guide future development of targeted therapeutic interventions for this debilitating respiratory disorder.
2026-07-14 | The association between chronic rhinosinusitis, bronchiectasis and type 2 inflammation: an EMBARC registry analysis.
Chronic rhinosinusitis (CRS) is a common comorbidity in bronchiectasis. Previous studies suggested that bronchiectasis with CRS is associated with elevated type 2 biomarkers, representing an "eosinophilic bronchiectasis" phenotype. However, whether the association with type 2 inflammation exists in rare aetiologies of bronchiectasis such as primary ciliary dyskinesia (PCD) or immune deficiency is unknown. Our aim was to explore the prevalence of CRS with and without nasal polyposis (CRSwNP and CRSnNP), their impact on bronchiectasis outcomes, and their association with type 2 inflammatory biomarkers in patients with bronchiectasis of various aetiologies. Using data from the EMBARC bronchiectasis registry, we classified patients with bronchiectasis as having no CRS, CRSnNP or CRSwNP. Regression models were used to test the effect of CRS on symptom scores and long-term outcomes. Multivariate models were created for elevated "type 2 biomarkers", defined as elevated blood eosinophil count or total IgE. Among 16 640 people with bronchiectasis, 2703 (20.9%) had CRSnNP and 1223 (7.3%) had CRSwNP. CRSwNP and CRSnNP were associated with worse symptoms and more frequent exacerbations, but lower hospitalisations and mortality. Type 2 biomarkers were elevated in people with comorbid CRSwNP in idiopathic bronchiectasis, but not in bronchiectasis secondary to PCD or immune deficiency. In multivariable analysis, CRSwNP was independently associated with elevated type 2 biomarkers. CRS and nasal polyposis are common comorbidities in bronchiectasis, associated with worse symptoms and exacerbations. Elevated type 2 biomarkers are associated with CRS, but this finding is dependent on the aetiology of bronchiectasis.
2026-06-15 | Sotatercept treatment in a patient with end-stage bronchiolitis obliterans syndrome after lung transplantation.
Bronchiolitis obliterans syndrome (BOS), the most common form of chronic lung allograft dysfunction after lung transplantation, is characterized by progressive small airway disease (SAD) and is associated with poor outcomes and limited therapeutic options. Sotatercept, an activin-signaling inhibitor approved for pulmonary arterial hypertension, has been associated with improvements in physiologic markers of SAD in patients with pulmonary hypertension. In this report, we describe a 55-year-old woman with primary ciliary dyskinesia status post bilateral lung transplantation who developed stage 3 BOS complicated by hypercapnic respiratory failure requiring mechanical ventilation. Following initiation of off-label sotatercept, she experienced rapid clinical and radiologic improvement, permitting transient liberation from mechanical ventilation before succumbing to progressive respiratory failure. Further study is required to assess the potential role for activin pathway modulation in advanced BOS.
gene therapies
2026-05-29 | A homozygous splicing mutation in CCDC39 caused multiple morphological abnormalities of the flagella in an infertile man with primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a severe sperm defect, leading to male infertility. PCD affects both respiratory function and sperm motility, as motile cilia and sperm flagella rely on axonemal architecture. Multiple morphological abnormalities of the sperm flagella (MMAF) is a distinct form of asthenoteratozoospermia, characterized by a heterogeneous spectrum of flagellar defects. In recent years, coiled-coil domain-containing (CCDC) genes have been shown to play crucial roles in both MMAF and PCD. In this study, a homozygous mutation in CCDC39, c.1528-2A>G, was identified in a patient of a consanguineous Chinese family presenting a typical PCD phenotype. Quantitative real-time polymerase chain reaction (qPCR) and immunofluorescence demonstrated a significant reduction in CCDC39 mRNA levels and loss of the expression of CCDC39 and other axoneme dynein proteins, respectively. Diff-Quik staining and semen analysis from the patient revealed severely reduced sperm motility, in addition to a pronounced MMAF phenotype. Severe axonemal disorganization and ultrastructural defects were consistent with the PCD phenotype in the patient, further suggesting that CCDC39 deficiency is linked to both infertility and systemic ciliary dysfunction. After intracytoplasmic sperm injection (ICSI) treatment, the CCDC39-deficient patient achieved a successful pregnancy. Overall, our findings clearly indicate that the c.1528-2A>G mutation in CCDC39 is associated with the pathogenesis of both MMAF and PCD, thereby advancing genetic diagnosis, treatment, and prognosis related to in vitro fertilization (IVF) outcomes associated with the MMAF phenotype in PCD patients.
2026-05-15 | Primary ciliary dyskinesia in pediatric persons: A microscopic movement malady.
The respiratory tract (i.e., airways and alveoli) is in close contact with the milieu that is outside the human body and thus, in addition to its role in exchange of gases, it is needed to protect the human being from outside threats such as microbes and pollution. Respiratory tract diseases can have major detrimental effects on human health with increased risks for morbidity and mortality. An example of this dilemma is the orphan disease, primary ciliary dyskinesia (PCD), a complex genetic disorder linked with myriad genetic mutations involving over 50 genes and over 2000 pathogenic variants that lead to dysfunction of vital human components including the respiratory tract, auditory system, mechanisms of fertility and others. The core defect involves abnormal function and motion of microscopic organelles called cilia found throughout the human body with abnormal mucociliary clearance (i.e., aberrant mucociliary escalator). The regulation of motile cilia that are involved in various aspects of physiology such as respiration and reproduction is via thousands of genes. PCD pathophysiology, genetic underpinnings, diagnosis and principles of treatment are considered in this review of primary ciliary dyskinesia in pediatric persons (i.e., newborns, children and adolescents). Primary ciliary dyskinesia (PCD) is one of many ciliopathies that is identified as a condition with remarkable phenotypic and genetic variability. In this fluid fluctuation phenomenon, some PCD patients exhibit classic features such as chronic respiratory disease, situs abnormalities, and infertility, while others may present with milder or atypical disease. In certain cases, ultrastructural analysis of cilia may appear normal despite underlying dysfunction. Disease severity can range from early-onset bronchiectasis to relatively preserved pulmonary function into adulthood, reflecting perplexing genotype-phenotype diversity. Testing for PCD requires an experienced team with expertise in sophisticated technology that includes nasal nitric oxide (nNO) analysis, transmission electron microscopy (TEM), immunofluorescence analysis (IFA), high-speed video-microscopy analysis (HSVMA), three-dimensional explant spheroid formation (3D-E; ex vivo technique), genetic studies and others. Genetic testing is recommended for those suspected of having PCD, as for example in certain neonates (i.e., persistent respiratory distress, unexplained rhinorrhea with chronic cough, situs inversus), at-risk children (i.e., having persistent wet cough, chronic sinusitis, unexplained bronchiectasis, recurrent otitis media with airway symptomatology) and adults with early childhood respiratory symptoms often associated with infertility. The medical evaluation is complicated by various factors including the absence of a gold standard for a precise diagnosis. Also, as the clinician or clinical team considers a patient with possible PCD, the testing that is done should keep in mind the differential diagnoses of PCD; these conditions include cystic fibrosis (CF), various immune disorders, numerous infections (i.e., tuberculosis, aspergillosis, others), alpha-1-antitrypsin deficiency (AATD) and others as noted in this article. As emerging cutting-edge 21st century research seeks treatment of PCD via gene therapy, current management involves intense therapy of upper and lower respiratory tract infections (i.e., rhinosinusitis, otitis media, pneumonia) as well as bronchiectasis with focused efforts at dealing with impaired mucus clearance. Primary ciliary dyskinesia is a classic example of how microscopic (electron microscopic) maladies can lead to major macroscopic maladies in newborns, children, adolescents and adults.
2026-04-29 | AAV-Mediated Base Editing for Correction of RSPH4A Mutations in Primary Ciliary Dyskinesia: A Proof-of-Concept Study.
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder, with abnormal ciliary motility, usually due to an ultrastructural defect, with chronic airway infections. Currently, no curative therapy exists for PCD. Given the prevalence of single nucleotide variants (SNVs) among causative mutations, we evaluated a novel base-editing approach. Specifically, we used a nickase Cas9 fused to adenosine deaminase to correct mutations in the radial spoke head component 4 A (RSPH4A) gene, causing PCD. We selected two PCD patients sharing the same SNV in RSPH4A, one with compound heterozygosity (child, patient 1) and one with homozygosity (adult, patient 2). After designing gRNAs, HEK293T cells with or without a DNA fragment containing the SNV in RSPH4A, were co-transfected with base editor plasmids. Complex formation and editing efficiency were validated by Western blot and digital PCR. We then treated patient cells with AAV containing the base editors and assessed ciliary beat frequency and motion pattern using high-speed video and confocal microscopy to evaluate delivery.Base editor complexes formed efficiently in vitro. AAV-mediated delivery in patient 1 cells led to an approximately 30.4% increase in normal motion pattern, with a corresponding reduction in circular motions (p < 0.001) compared with pre-treatment, and a 20% of editing efficiency detected by dPCR in transduced cells. Our data indicate that this limited editing efficiency is due to reduced AAV penetration in the lower layers of cells.This proof-of-concept study demonstrates the therapeutic potential of base editing for PCD, though current limitations include low editing efficiency and restricted delivery to inner cell layers in our experimental model. Future work should focus on optimizing base editors and testing novel delivery strategies to target progenitor cells, thereby enhancing the prospects for personalized gene therapy in PCD.
2026-02-27 | Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by defective motile cilia and impaired mucociliary clearance. Mutations in CCDC40 disrupt axonemal organization, resulting in dyskinetic or immotile cilia. While emerging therapies may restore function in only a subset of cells, the functional consequences of mixed populations of mutant and healthy cilia are not well understood. To determine how defined mixtures of CCDC40-deficient and wild-type ciliated cells influence mucociliary transport. Human bronchial epithelial cells were combined at varying ratios of CCDC40-deficient and wild-type cells and differentiated to model heterogeneous epithelia. High-speed video microscopy and particle-tracking algorithms were used to assess ciliary motion and mucus transport and combined with electron microscopy to evaluate cilia ultrastructure. Airway differentiation was largely preserved with marked ultrastructural defects observed in CCDC40 cells, including multiple central centrioles, absent inner dynein arms, and basal body misorientation. Ciliated surface coverage decreased, and goblet coverage increased with higher mutant representation. Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures. Clearance-per-beat and flow coordination decreased sharply with rising mutant burden. Modeling revealed that transport efficiency was equivalent to that recorded in ex vivo human tissues and plateaued when ~75% of the ciliated population was WT. Together, these findings define a PCD-specific functional correction threshold and show that effective therapy must overcome the disruptive biomechanical and cellular influences of mutant epithelial cells, providing a quantitative benchmark to guide gene-therapy design and clinical translation.
2026-02-06 | Compound heterozygous DAW1 variants reveal tissue-specific roles in left-right patterning and congenital heart disease without primary ciliary dyskinesia.
Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with HTX and complex congenital heart disease but no clinical signs of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1G>A) and a paternally inherited missense variant (c.341G>A; p.Arg114Gln), both classified as variants of uncertain significance under ACMG/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln fully rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1G>A as pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.
other
2025-05-01 | Antigen Stasis and Increased IL-33 Activation in the Human Primary Ciliary Dyskinesia Epithelium
Abstract Introduction. Antigen stasis on dysfunctional cilia leads to oxidative stress and DUOX1 activation in human primary ciliary dyskinesia (PCD) cells grown at air liquid interface (ALI) (PMID: 38318660). Activated DUOX-1 can increase epithelial activation of the alarmin IL-33, which binds to ST2 receptors (PMID: 27812543) on inflammatory cells, releasing cytokines associated with asthma. Recent publications suggest that a majority of patients with PCD may also have asthma. However, IL33 has not previously been studied in the PCD epithelium. Materials and methods. Primary nasal epithelial cell (normal HC – healthy control and PCD) grown to full ciliation at ALI included two biologic replicates from patients with PCD (genotypes DNAH11 and DNAH5) and from two healthy control (HC) subjects (all four are male). The ratio of cleaved (activated)/full length (CL/FL) IL-33 was measured in cell lysate and in the basolateral cell media four hours after a medium change. Immunoblot was carried out using the Jess (Protein Simple) 24 lane system and an optimized rabbit monoclonal antibody (E2TSL #88513; Cell Signaling). We also performed an ELISA assay (R/D Systems Cat # D3300B), comparing cellular to released IL33, in the presence and absence of the common asthma-associated antigen, Derp1. Results. By immunoblot, IL33 activation (CL/FL IL-33 ratio) was higher in PCD epithelial cell media than HC cells (p < 0.0001), but not in the cell lysates (Figure). Derp-1 treatment of PCD airway epithelial cells at ALI (3 technical replicates each) with or without Derp1 (active; 2 h) revealed that PCD cells release more activated IL33 after 4 hr Derp1 exposure than do baseline PCD cells or HC cells. (p < 0.05). Conclusions. Activation and release of the asthma-associated alarmin, IL33, is increased in primary human airway epithelial cells at ALI patients with PCD, an effect increased by apical antigen. It will be important to study the downstream immunology to ascertain whether this increased IL33 activation contributes to an asthma-like phenotype in patients with PCD. IL33 and downstream mediators may ultimately prove to be suitable targets for PCD treatment.
2024-08-17 | A 3000-year-old founder variant in the DRC1 gene causes primary ciliary dyskinesia in Japan and Korea.
Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by ciliary structural abnormalities and dysfunction, leading to chronic rhinosinusitis, otitis media with effusion, bronchiectasis, and infertility. Approximately half of Japanese PCD cases are attributed to variants in the dynein regulatory complex subunit 1 (DRC1) gene, predominantly featuring homogeneous deletions of exons 1-4 spanning 27,748 base pairs on chromosome 2. Here, we report 10 new PCD cases (9 families) in addition to 29 previously reported cases (24 families) caused by DRC1 variants. Among these 39 cases, biallelic DRC1 exon 1-4 deletions were detected in 38 (97.4%). These DRC1 deletions exhibited an identical breakpoint in all PCD cases in the Japanese and Korean populations, strongly suggesting a founder effect. In this study, we performed haplotype analysis, using a whole-exome sequencing dataset of 18 Japanese PCD patients harboring large biallelic DRC1 deletions. We estimated that the founder allele likely emerged 115.1 generations ago (95% confidence interval: 33.7-205.1), suggesting an origin of approximately 3050 years ago, coinciding with the transition from the Jomon period to the early Yayoi period in Japan. Considering the formation of the modern Japanese population, the founder with the DRC1 exon 1-4 deletion likely lived on the Korean peninsula, with the allele later transmitted to Japan through migration. This study provides insights into the origin of the DRC1 copy number variant, the most frequent PCD variant in the Japanese and Korean populations, highlighting the importance of understanding population-specific genetic variations in the context of human migration and disease prevalence.
2023-12-16 | Airway microbiota correlated with pulmonary exacerbation in primary ciliary dyskinesia patients.
PCD is a rare disease characterized by productive cough, rhinitis, and recurrent infections of the upper and lower airways. Because the diagnosis of PCD is often delayed, patients receive more antibiotics, experience a heavier financial burden, and have a worse prognosis; thus, it is very important to identify the pathogeny and use the correct antibiotic. In this large single-center study of PCD microbiota, we identified an outline of the bacterial microbes from the respiratory tract; furthermore, we found that the microbiota diversity in pediatric sputum was richer than that in pediatric BALF through sequencing, indicating a heterogeneous community structure. The microbiota diversity and richness were lower during pulmonary exacerbation than during pulmonary stabilization. A significantly higher abundance of Pseudomonas had a moderate distinguishing effect for lung exacerbation, which attracted more attention for the study of Pseudomonas therapy in pediatric patients with PCD.
2023-08-04 | RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis
A core pathophysiologic feature underlying many respiratory diseases is multiciliated cell dysfunction, leading to inadequate mucociliary clearance. Due to the prevalence and highly variable etiology of mucociliary dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in a complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelia, however this does not apply to all cell types, nor does it occur evenly across all cells in the same cell population. In this study we further investigated how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells, we identify RBL2 as a repressor of the transcriptional activity of Multicilin. Knockdown of RBL2 in submerged cultures or phosphorylation of RBL2 in response to apical air exposure, in the presence of Multicilin, allows multiciliogenesis to progress. These data demonstrate a dynamic interaction between RBL2 and Multicilin that regulates the capacity of cells to differentiate and multiciliate. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases with impaired mucociliary clearance.
2022-04-18 | Genes associated with situs inversus in patients with primary ciliary dyskinesia are identified by the weighted gene correlation network analysis
Abstract Background. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by immotile and dysmotile cilia or absence of cilia. Situs inversus (SI) is one of the phenomena frequently observed in PCD. However, little is known about the association between SI with PCD. Material and Methods. The microarray data of PCD were retrieved from the Gene Expression Omnibus (GEO) database to construct the co-expression network by the weighted gene co-expression network analysis (WGCNA). R software package Limma was used to perform the differential analysis. The gene network modules associated with SI screened with the common genes were further annotated based on Gene Ontology (GO) database and enriched based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Gene Set Enrichment Analysis (GSEA) was applied to identify the significant pathways. CIBERSORT was used to perform the correlation analysis of immune cells. The protein-protein interaction (PPI) network was constructed based on STRING database to identify the hub genes in the network. Results. Genes involved in PCD were identified related to SI. The results of the correlation analysis of immune cells showed that there were significant differences in the activated contents of dendritic cells. The WGCNA analysis revealed a total of 8 hub genes (i.e., ATP5A1, NDUFS3, NDUFV2, PSMC3, UBE2M, ALDH18A1, DBT, FOXRED1 ). Based on the GO annotations of hub genes, a group of GO terms were revealed to show significant difference, including mitochondrial part, oxidoreductase complex, cytosol, mitochondrial respiratory chain complex I, NADH dehydrogenase complex, respiratory chain complex I, catalytic complex, mitochondrial envelope, respiratory chain complex, and mitochondrial respiratory chain. KEGG enrichment analysis of hub genes identified a group of metabolic pathways showing significant difference, including Propanoate metabolism, beta-Alanine metabolism, Fatty acid degradation, Valine, leucine and isoleucine degradation, Huntington disease, Carbon metabolism, Fatty acid metabolism, Lysine degradation, Butanoate metabolism, and Metabolic pathways. Conclusion. Our study identified the variations in immune cells in PCD patients. The hub genes provide novel therapeutic targets for the diagnosis and treatment of PCD and SI.
small molecules
2026-09-10 | Amiloride mitigates respiratory distress caused by WFDC2 deficiency via inhibiting the epithelial sodium channel.
Chronic airway diseases such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) pose substantial clinical challenges. Here, we explore the p.C97W variant in WAP four-disulfide core domain protein 2 (WFDC2), proposed as a new genetic origin of respiratory distress, especially among Koreans. Whole-exome and whole-genome sequencing (WES/WGS) are performed on 64 patients from 62 families presenting with severe bronchiectasis and chronic rhinosinusitis. Pathogenic variants are found in 19.4% of families, including a novel homozygous WFDC2 missense variant (c.291 C > G, p.Cys97Trp) in five unrelated families. WFDC2 is expressed in lung epithelial cells, and the p.C97W variant impairs WFDC2 protein folding, secretion, and function. Wfdc2 p.C147W knock-in mice exhibit respiratory failure due to the hyperactive epithelial sodium channel (ENaC) linked to increased PRSS8 activity and recapitulate human disease. Treatment with amiloride, an ENaC inhibitor, improves survival and respiratory function in these mice. In conclusion, the p.C97W variant in WFDC2 is a critical genetic factor in severe chronic airway disease that shares clinical features with CF and PCD. Given its implications for diagnosis and treatment, genetic testing for WFDC2 mutations in individuals with CF- or PCD-like symptoms is recommended.
2026-09-07 | Pulmonary exacerbations in primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction characterized by impaired mucociliary clearance, chronic sino-pulmonary disease, and progressive bronchiectasis. Pulmonary exacerbations (PEx) are a major contributor to morbidity, lung function decline, and healthcare utilization in PCD, yet historically have been poorly defined and understudied. This review summarizes current evidence regarding the definition, epidemiology, pathophysiology, clinical impact, and management of PEx in PCD, with emphasis on recent advances that are beginning to establish a disease-specific evidence base. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. Prospective cohort data demonstrate that PEx occur frequently across all age groups, including infancy, and are associated with impaired lung function recovery, structural lung damage, and increased disease severity, particularly in patients with chronic Pseudomonas aeruginosa infection. Emerging biomarkers such as lung clearance index and exhaled breath analysis using volatile organic compounds may improve prediction and monitoring of exacerbations. Management strategies currently rely largely on extrapolation from cystic fibrosis and non-cystic fibrosis bronchiectasis and include prompt antibiotic therapy, intensified airway clearance, and supportive care. However, recent randomized controlled trials, including BESTCILIA and CLEAN-PCD, have provided the first high-quality evidence supporting maintenance azithromycin therapy and airway hydration strategies in PCD. Despite these advances, important gaps remain regarding optimal exacerbation definitions, treatment duration, predictors of incomplete recovery, and the role of anti-inflammatory and targeted therapies. Continued international collaboration, validated outcome measures, and development of mechanism-based therapies will be essential to improve long-term outcomes for patients with PCD. • Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction causing chronic sino-pulmonary disease, recurrent respiratory infections, and progressive bronchiectasis from early childhood. • Pulmonary exacerbations (PEx) are a major driver of morbidity and lung function decline in PCD, but have historically been inconsistently defined and understudied, with management largely extrapolated from cystic fibrosis and non-CF bronchiectasis. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. • Prospective international cohort data (Schreck et al. 2026) establish a PEx incidence of approximately 3.1 per person per year across all age groups, with higher risk in adult females and Pseudomonas aeruginosa-colonized patients. PEx are frequent even in the first 2 years of life. Pulmonary exacerbations cause substantial acute loss in forced expiratory volume in 1 s (FEV1), and approximately 20-25% of events do not recover to baseline lung function. • The BESTCILIA trial provides the first high-quality evidence that maintenance azithromycin reduces PEx frequency by 55% in PCD, and the CLEAN-PCD trial provides proof-of-concept for airway rehydration (ENaC blockade + hypertonic saline) as a PCD-specific therapeutic strategy.Novel anti-inflammatory therapies (DPP1 inhibitors, neutrophil elastase inhibitors), inhaled biologics, and gene-directed strategies are entering the PCD therapeutic pipeline and may transform future PEx prevention.
2026-08-22 | Evaluating the efficacy and safety of macrolide therapy in primary ciliary dyskinesia: A systematic review.
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired ciliary function, defective mucociliary clearance, recurrent respiratory infections, and progressive respiratory morbidity. Macrolides, particularly azithromycin, have antibacterial, anti-inflammatory, and immunomodulatory properties and may therefore provide therapeutic benefit in PCD. This systematic review evaluated the efficacy and safety of macrolide therapy in patients with PCD. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and was prospectively registered in International Prospective Register of Systematic Reviews (CRD42024553793). PubMed, Scopus, Web of Science, Embase, Cochrane, and Google Scholar were searched for studies published from January 1, 1990, to June 18, 2024. Eligibility criteria were defined using the population, intervention, comparator, outcomes, and study design framework. Study selection, data extraction, and risk of bias assessment were performed independently by 3 reviewers. A meta-analysis was not performed because of substantial methodological heterogeneity across the included studies. Of 765 records identified, 9 studies met the inclusion criteria. These included 2 in vitro studies and 7 clinical studies, comprising case reports, case series, retrospective observational studies, and 1 randomized, placebo-controlled phase 3 trial. Across the clinical studies, sample sizes ranged from 1 to 90 participants. Overall, the available evidence suggested that macrolide therapy, particularly azithromycin, may reduce respiratory exacerbations and improve selected clinical symptoms in patients with PCD. Mechanistic in vitro evidence further indicated that azithromycin may reduce pro-inflammatory cytokine production and promote epithelial barrier repair. However, the included studies varied considerably in design, population characteristics, treatment protocols, and outcome definitions. Macrolides, especially azithromycin, may have a beneficial role in the management of PCD by reducing respiratory exacerbations, improving selected symptoms, and modulating airway inflammation. Nevertheless, the certainty of evidence remains limited by methodological heterogeneity, small sample sizes, and the scarcity of randomized controlled trials. Further large-scale, well-designed, PCD-specific clinical studies are required to confirm these preliminary findings and establish standardized treatment protocols.
2026-08-18 | Clinical features, misdiagnosis, and treatment of clinically diagnosed complete Kartagener syndrome: A three-case series for primary care.
Kartagener syndrome (KS) is a rare autosomal recessive motile ciliopathy and a well-recognized subtype of primary ciliary dyskinesia, classically defined by the triad of situs inversus totalis, chronic sinusitis, and bronchiectasis, with frequent accompanying infertility. Because of its non-specific clinical manifestations overlapping with common respiratory disorders and limited availability of gold-standard diagnostic tools in primary care settings, KS is frequently misdiagnosed or diagnosed late. This study retrospectively analyzed the clinical data, diagnostic trajectories, and treatment outcomes of three adult patients with clinically diagnosed complete KS admitted to our institution between May 2021 and December 2022. All patients presented with long-standing recurrent cough and expectoration; two presented with hemoptysis and one with type II respiratory failure. Initial misdiagnoses included bronchiectasis, non-tuberculous mycobacterial infection, and chronic obstructive pulmonary disease. Clinical diagnosis of complete KS was established based on the classic triad on imaging combined with core clinical features, as confirmatory genetic or ultrastructural testing was not available. Pathogen testing detected Acinetobacter baumannii in one patient, while another patient had a coinfection of Pseudomonas aeruginosa and Enterobacter cloacae. One more patient received empirical antimicrobial therapy because their family declined bronchoscopy. After individualized treatment, clinical improvement was observed in all patients, with symptom resolution, normalized inflammatory markers, and stable disease during 6-12 months of follow-up. These findings underscore that the combined features of "situs inversus totalis + bronchiectasis + chronic sinusitis + childlessness/infertility (when formally confirmed)" are key diagnostic clues for KS in primary care. Primary care clinicians should strengthen awareness of this rare entity and use a multisystem diagnostic approach to prevent misdiagnosis and underdiagnosis. Prompt targeted antimicrobial therapy and sustained comprehensive long-term management were associated with favorable clinical outcomes in this small case series.
2026-06-01 | High-dose continuous infusion of piperacillin/tazobactam via elastomeric pump in a pediatric patient with Kartagener syndrome: pharmacokinetic target attainment and clinical outcome.
Multidrug-resistant Achromobacter xylosoxidans infections in pediatric patients with primary ciliary dyskinesia (PCD) often require prolonged intravenous therapy. We evaluated the pharmacokinetics of continuous infusion piperacillin/tazobactam (16 g/2 g daily) in a 13-year-old male with situs inversus and chronic otitis media transitioned from hospital-based electronic infusion to home-based Outpatient Parenteral Antimicrobial Therapy (OPAT) using elastomeric pumps. Plasma concentrations were measured by Therapeutic Drug Monitoring (TDM), and tissue exposure was estimated using conservative penetration coefficients. Drug concentrations consistently remained above the MIC (≤2 mg/L). During hospitalization, steady-state concentrations were stable (27.2-29.0 mg/L; CV 4.5%), whereas during OPAT they were higher and more variable (53.9-80.1 mg/L; CV 20.1%), consistent with the known non-linear delivery profiles of elastomeric devices. Despite this variability, TDM confirmed sustained supratherapeutic exposure, with estimated tissue concentrations remaining >5-fold above the MIC. Clinical resolution was achieved without adverse events, supporting the role of TDM-guided OPAT in difficult-to-treat infections.
cell therapies
2026-03-30 | [Normal Delivery by Intracytoplasmic Sperm Injection with Epididymal Sperm in a Patient with Azoospermia and Kartagener Syndrome].
Kartagener syndrome is defined as a primary ciliary dyskinesia with visceral inversion, bronchiectasis, and chronic sinusitis. Male patients with primary ciliary dyskinesia including Kartagener syndrome are also associated with male infertility, mainly because of sperm tail immobility. We report a case in a 36-year-old man with Kartagener syndrome and azoospermia. An examination indicated obstructive azoospermia. Therefore, testicular sperm extraction and microsurgical epididymal sperm aspiration were performed, and sperm retrieval was successful. Motile epididymal spermatozoa were used for the first intracytoplasmic sperm injection, and a single embryo was transferred. The course of pregnancy was uneventful and a healthy boy was delivered. Intracytoplasmic sperm injection following microsurgical epididymal sperm aspiration is an effective treatment for infertility due to Kartagener syndrome.
2026-03-21 | Deuterosomal cells are the responsible lineage for multiciliogenesis in human airway differentiation.
Multiciliated cells (MCCs) are pivotal in airway defense via their motile cilia to eliminate inhaled pathogens and particles. Genetic variants in primary ciliary dyskinesia (PCD) disrupt ciliary function, resulting in chronic respiratory infections. The formation of MCCs requires centriole amplification mediated by non-membranous organelles called deuterosomes, whose regulatory mechanisms remain poorly characterized in humans. Single-cell transcriptomic analyses have identified "deuterosomal cells" (DCs), a transient cell population that emerges during multiciliogenesis. DCs are challenging to investigate owing to their scarcity. To elucidate the role of DCs, iPSC-derived airway epithelial cells were used to identify CD36 as a specific surface marker. Furthermore, iPSCs were established from a patient with PCD harboring Cyclin O (CCNO) variants, along with gene-corrected controls. Patient-derived iPSCs demonstrated defective MCC differentiation and aberrant DCs attributed to CCNO deficiency. This study provides a human iPSC-based platform for investigating the mechanisms underlying airway multiciliogenesis and PCD modeling.
2025-04-01 | Combined cellular and gene therapy to treat primary ciliary dyskinesia
Primary Ciliary Dyskinesia (PCD) is a genetic disease caused by mutations that alter cilia beating, including in the respiratory airways. This results in poor mucus clearance, severe morbidity, and increased mortality. We hypothesized that bronchial cilia beating can be restored using genetically corrected iPSC differentiated into air - liquid interface bronchial epithelium model (iALI) for autologous cell therapy. We have previously demonstrated that corrected cells derived from a PCD patient iPS line can be differentiated into iALI with functional ciliary beating. The current aim of the project is to evaluate the engraftment potential of these corrected cells and their ability to repair the pathological model post-engraftment. Several key issues need to be addressed identifying competent cells for bronchial engraftment, exploring various strategies to pre-treat the bronchial epithelium, and assessing the recovery of the ciliary beating recovery to assure bronchial repair. Our team has established the differentiation of iPSCs into iALI. We have generated a PCD patient iPSC line using Sendai viruses, a corresponding CRISPR/Cas9 corrected cell line, as well a wild-type iPSC line and its CRISPR/Cas9 mutated counterpart. We also generated a GFP-iPSC line that expresses the fluorescent GFP protein under the human elongation factor 1 alpha promoter (EF1a), which allows us to track the engraftment of GFP-labeled bronchial stem cells in both control and mutated iALI models. Our results suggest that lung progenitors at the ventralized anterior foregut endoderm stage could be the most efficient cells for engraftment. Their self-renewal capability and ability to differentiate into various cell types of the bronchial epithelium are promising for developing a long-term and effective therapy. Regarding bronchial erosion, we found that promoting cell engraftment is crucial due to the barrier function of the intact bronchial epithelium and the lack of selective advantage of corrected cells. Various chemical and enzymatic strategies have shown potential, but their safety for in-vivo use needs further assessment. Furthermore, GFP-expressing engrafted cells displaying cilia suggest successful differentiation into ciliated cells, though functional recovery still requires confirmation. In conclusion, the engraftment of corrected lung progenitors into eroded bronchial epithelium appears to be a promising therapeutic strategy to PCD. Next step of the project involves developing this therapy for in-vivo application, assessing its safety and efficacy in an immunodeficient mini-pig model.
2024-11-28 | Targeted pre-conditioning and cell transplantation in the murine lower respiratory tract.
Transplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary- and pluripotent stem cell (PSC)-derived basal cells to efficiently engrai into the mouse trachea aier injury. However, there are many hurdles to overcome in translating these approaches to humans including developing safe and efficient methods for delivery in larger animal models. We propose a model which targets preconditioning and cell-delivery to the intrapulmonary airways utilizing a micro- bronchoscope for delivery. The detergent polidocanol was adapted for distal lung pre-conditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24-hours post-delivery. While initial re- epithelialization of airways occurred later than tracheas, complete repair was observed within 7-days. Both PSC-derived and primary basal cells delivered via micro-bronchoscope post-polidocanol injury engraied in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted pre-conditioning and cell delivery to the conducting intra- pulmonary airways, providing an important framework for pre-clinical translation of approaches for engineered airway epithelial regeneration.
2024-11-06 | Life-long functional regeneration of in vivo airway epithelium by the engraftment of airway basal stem cells.
Durable and functional regeneration of the airway epithelium in vivo with transplanted stem cells has the potential to reconstitute healthy tissue in diseased airways, such as in cystic fibrosis or primary ciliary dyskinesia. Here, we present detailed protocols for the preparation and culture expansion of murine primary and induced pluripotent stem cell-derived airway basal stem cells (iBCs) and methods for their intra-airway transplantation into polidocanol-conditioned murine recipients to achieve durable in vivo airway regeneration. Reconstitution of the airway tissue resident epithelial stem cell compartment of immunocompetent mice with syngeneic donor cells leverages the extensive self-renewal and multipotent differentiation properties of basal stem cells (BCs) to durably generate a broad diversity of mature airway epithelial lineages in vivo. Engrafted donor-derived cells re-establish planar cell polarity as well as functional ciliary transport. By using this same approach, human primary BCs or iBCs transplanted into NOD-SCID gamma recipient mice similarly display engraftment and multilineage airway epithelial differentiation in vivo. The time to generate mouse or human iBCs takes ~60 d, which can be reduced to ~20 d if previously differentiated cells are thawed from cryopreserved iBC archives. The tracheal conditioning regimen and cell transplantation procedure is completed in 1 d. A competent graduate student or postdoctoral trainee should be able to perform the procedures listed in this protocol.
proteins
2026-09-23 | Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.
Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with an HTX/laterality defect spectrum, presenting with complex CHD without extracardiac organ malposition and no evidence of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1 G > A, chr2:227,903,110 G > A (GRCh38)) and a paternally inherited missense variant (c.341 G > A; p.Arg114Gln, chr2: 227,893,818 G > A (GRCh38)), both classified as variants of uncertain significance under ACMG/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1 G > A as likely pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.
2026-09-07 | Clinical Outcomes of Chronic Airway Infection in Primary Ciliary Dyskinesia.
Primary ciliary dyskinesia (PCD) is a rare disorder of impaired respiratory mucociliary clearance and chronic pulmonary infections. The clinical impact of chronic infection is poorly understood. The objective of this single-center, retrospective cohort study was to assess clinical outcomes of people with PCD and chronic airway infection. We hypothesized that chronic airway infection would be associated with greater declines in lung function and higher pulmonary exacerbation rates. Linear mixed effects models were used to analyze the association of chronic infection with percent predicted forced expiratory volume in 1 s (ppFEV1). Poisson mixed models were used to analyze the association of chronic infection with exacerbation rates. Thirty-two people with PCD were included: 19 (59%) with chronic infection including 5 (16%) with chronic Pseudomonas aeruginosa (PA), 10 (31%) with chronic Haemophilus influenzae (HI), 2 (6%) with chronic methicillin-sensitive Staphylococcus aureus (MSSA) and 2 (6%) with chronic Aspergillus fumigatus (AF). A lower ppFEV1 was associated with chronic AF, but not with other chronic infections. The exacerbation rate ratio was 1.29 [95% CI 0.72, 2.30] (p = 0.388), 5.03 [95% CI 1.41, 18.0] (p = 0.013), 0.41 [95% CI 0.16, 1.08] (p = 0.072) and 2.19 [95% CI 0.39, 12.30] (p = 0.373) after development of chronic HI infection, chronic PA infection, chronic MSSA infection and chronic AF infection, respectively. In this single-center, retrospective study of chronic airway infections in PCD, chronic infection with PA was associated with a greater rate of pulmonary exacerbations but ppFEV1 decline was only associated with chronic AF infection.
2026-07-22 | Biallelic RSPH4A loss-of-function variants cause primary ciliary dyskinesia in a Chinese patient.
Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by defective motile cilia function, affecting approximately one in 7,500 to one in 10,000 live births. Pathogenic variants in radial spoke head genes, including RSPH4A, cause PCD with distinctive central-microtubular-pair defects. However, the functional consequences of novel RSPH4A variants remain poorly characterized, limiting genetic counseling and prenatal diagnostic capabilities. This study aims to reveal the genetic etiology of PCD in an affected family and the clinical significance of the two novel RSPH4A variants identified in this PCD-affected pedigree. We recruited a five-member Chinese family including an 11-year-old female PCD proband presenting with chronic bronchiectasis and recurrent respiratory infections. Comprehensive clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed to identify genetic variants. Bioinformatics analyses including protein sequence alignment and structural modeling were conducted. Experimental validation employed site-directed mutagenesis, quantitative real-time PCR, and Western blotting in HEK293T cells to characterize variant effects on mRNA stability and protein expression. WES identified compound heterozygous RSPH4A variants in the proband: RSPH4A (NM_001010892.3): c.2T>C (p.Met1Thr) inherited from the mother and RSPH4A (NM_001010892.3): c.854delA (p.Lys286Serfs*22) inherited from the father, showing strict co-segregation with the disease phenotype. The c.2T>C variant disrupted the translation initiation codon, while c.854delA introduced a premature termination codon within the radial spoke head domain. Cross-species analysis demonstrated high conservation of the affected region across 15 vertebrate species. Structural modeling predicted complete loss of the radial spoke head domain in the truncated protein. Functional studies revealed that c.2T>C severely impaired protein translation despite intact mRNA levels, whereas c.854delA triggered nonsense-mediated mRNA decay and produced unstable truncated protein. Both variants resulted in substantial reduction in functional RSPH4A protein expression. This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies. These findings offer compelling proof in favor of a molecular diagnosis of PCD in this family and enable carrier screening for at-risk relatives. The experimental validation strategy establishes a framework for interpreting variants of uncertain significance in PCD genes, facilitating accurate prenatal diagnosis and preimplantation genetic testing to reduce the recurrence risk and birth defect incidence in PCD. Furthermore, understanding the precise functional consequences of RSPH4A variants informs genotype-phenotype correlations and may guide future development of targeted therapeutic interventions for this debilitating respiratory disorder.
2026-07-14 | The association between chronic rhinosinusitis, bronchiectasis and type 2 inflammation: an EMBARC registry analysis.
Chronic rhinosinusitis (CRS) is a common comorbidity in bronchiectasis. Previous studies suggested that bronchiectasis with CRS is associated with elevated type 2 biomarkers, representing an "eosinophilic bronchiectasis" phenotype. However, whether the association with type 2 inflammation exists in rare aetiologies of bronchiectasis such as primary ciliary dyskinesia (PCD) or immune deficiency is unknown. Our aim was to explore the prevalence of CRS with and without nasal polyposis (CRSwNP and CRSnNP), their impact on bronchiectasis outcomes, and their association with type 2 inflammatory biomarkers in patients with bronchiectasis of various aetiologies. Using data from the EMBARC bronchiectasis registry, we classified patients with bronchiectasis as having no CRS, CRSnNP or CRSwNP. Regression models were used to test the effect of CRS on symptom scores and long-term outcomes. Multivariate models were created for elevated "type 2 biomarkers", defined as elevated blood eosinophil count or total IgE. Among 16 640 people with bronchiectasis, 2703 (20.9%) had CRSnNP and 1223 (7.3%) had CRSwNP. CRSwNP and CRSnNP were associated with worse symptoms and more frequent exacerbations, but lower hospitalisations and mortality. Type 2 biomarkers were elevated in people with comorbid CRSwNP in idiopathic bronchiectasis, but not in bronchiectasis secondary to PCD or immune deficiency. In multivariable analysis, CRSwNP was independently associated with elevated type 2 biomarkers. CRS and nasal polyposis are common comorbidities in bronchiectasis, associated with worse symptoms and exacerbations. Elevated type 2 biomarkers are associated with CRS, but this finding is dependent on the aetiology of bronchiectasis.
2026-06-15 | Sotatercept treatment in a patient with end-stage bronchiolitis obliterans syndrome after lung transplantation.
Bronchiolitis obliterans syndrome (BOS), the most common form of chronic lung allograft dysfunction after lung transplantation, is characterized by progressive small airway disease (SAD) and is associated with poor outcomes and limited therapeutic options. Sotatercept, an activin-signaling inhibitor approved for pulmonary arterial hypertension, has been associated with improvements in physiologic markers of SAD in patients with pulmonary hypertension. In this report, we describe a 55-year-old woman with primary ciliary dyskinesia status post bilateral lung transplantation who developed stage 3 BOS complicated by hypercapnic respiratory failure requiring mechanical ventilation. Following initiation of off-label sotatercept, she experienced rapid clinical and radiologic improvement, permitting transient liberation from mechanical ventilation before succumbing to progressive respiratory failure. Further study is required to assess the potential role for activin pathway modulation in advanced BOS.
gene therapies
2026-05-29 | A homozygous splicing mutation in CCDC39 caused multiple morphological abnormalities of the flagella in an infertile man with primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a severe sperm defect, leading to male infertility. PCD affects both respiratory function and sperm motility, as motile cilia and sperm flagella rely on axonemal architecture. Multiple morphological abnormalities of the sperm flagella (MMAF) is a distinct form of asthenoteratozoospermia, characterized by a heterogeneous spectrum of flagellar defects. In recent years, coiled-coil domain-containing (CCDC) genes have been shown to play crucial roles in both MMAF and PCD. In this study, a homozygous mutation in CCDC39, c.1528-2A>G, was identified in a patient of a consanguineous Chinese family presenting a typical PCD phenotype. Quantitative real-time polymerase chain reaction (qPCR) and immunofluorescence demonstrated a significant reduction in CCDC39 mRNA levels and loss of the expression of CCDC39 and other axoneme dynein proteins, respectively. Diff-Quik staining and semen analysis from the patient revealed severely reduced sperm motility, in addition to a pronounced MMAF phenotype. Severe axonemal disorganization and ultrastructural defects were consistent with the PCD phenotype in the patient, further suggesting that CCDC39 deficiency is linked to both infertility and systemic ciliary dysfunction. After intracytoplasmic sperm injection (ICSI) treatment, the CCDC39-deficient patient achieved a successful pregnancy. Overall, our findings clearly indicate that the c.1528-2A>G mutation in CCDC39 is associated with the pathogenesis of both MMAF and PCD, thereby advancing genetic diagnosis, treatment, and prognosis related to in vitro fertilization (IVF) outcomes associated with the MMAF phenotype in PCD patients.
2026-05-15 | Primary ciliary dyskinesia in pediatric persons: A microscopic movement malady.
The respiratory tract (i.e., airways and alveoli) is in close contact with the milieu that is outside the human body and thus, in addition to its role in exchange of gases, it is needed to protect the human being from outside threats such as microbes and pollution. Respiratory tract diseases can have major detrimental effects on human health with increased risks for morbidity and mortality. An example of this dilemma is the orphan disease, primary ciliary dyskinesia (PCD), a complex genetic disorder linked with myriad genetic mutations involving over 50 genes and over 2000 pathogenic variants that lead to dysfunction of vital human components including the respiratory tract, auditory system, mechanisms of fertility and others. The core defect involves abnormal function and motion of microscopic organelles called cilia found throughout the human body with abnormal mucociliary clearance (i.e., aberrant mucociliary escalator). The regulation of motile cilia that are involved in various aspects of physiology such as respiration and reproduction is via thousands of genes. PCD pathophysiology, genetic underpinnings, diagnosis and principles of treatment are considered in this review of primary ciliary dyskinesia in pediatric persons (i.e., newborns, children and adolescents). Primary ciliary dyskinesia (PCD) is one of many ciliopathies that is identified as a condition with remarkable phenotypic and genetic variability. In this fluid fluctuation phenomenon, some PCD patients exhibit classic features such as chronic respiratory disease, situs abnormalities, and infertility, while others may present with milder or atypical disease. In certain cases, ultrastructural analysis of cilia may appear normal despite underlying dysfunction. Disease severity can range from early-onset bronchiectasis to relatively preserved pulmonary function into adulthood, reflecting perplexing genotype-phenotype diversity. Testing for PCD requires an experienced team with expertise in sophisticated technology that includes nasal nitric oxide (nNO) analysis, transmission electron microscopy (TEM), immunofluorescence analysis (IFA), high-speed video-microscopy analysis (HSVMA), three-dimensional explant spheroid formation (3D-E; ex vivo technique), genetic studies and others. Genetic testing is recommended for those suspected of having PCD, as for example in certain neonates (i.e., persistent respiratory distress, unexplained rhinorrhea with chronic cough, situs inversus), at-risk children (i.e., having persistent wet cough, chronic sinusitis, unexplained bronchiectasis, recurrent otitis media with airway symptomatology) and adults with early childhood respiratory symptoms often associated with infertility. The medical evaluation is complicated by various factors including the absence of a gold standard for a precise diagnosis. Also, as the clinician or clinical team considers a patient with possible PCD, the testing that is done should keep in mind the differential diagnoses of PCD; these conditions include cystic fibrosis (CF), various immune disorders, numerous infections (i.e., tuberculosis, aspergillosis, others), alpha-1-antitrypsin deficiency (AATD) and others as noted in this article. As emerging cutting-edge 21st century research seeks treatment of PCD via gene therapy, current management involves intense therapy of upper and lower respiratory tract infections (i.e., rhinosinusitis, otitis media, pneumonia) as well as bronchiectasis with focused efforts at dealing with impaired mucus clearance. Primary ciliary dyskinesia is a classic example of how microscopic (electron microscopic) maladies can lead to major macroscopic maladies in newborns, children, adolescents and adults.
2026-04-29 | AAV-Mediated Base Editing for Correction of RSPH4A Mutations in Primary Ciliary Dyskinesia: A Proof-of-Concept Study.
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder, with abnormal ciliary motility, usually due to an ultrastructural defect, with chronic airway infections. Currently, no curative therapy exists for PCD. Given the prevalence of single nucleotide variants (SNVs) among causative mutations, we evaluated a novel base-editing approach. Specifically, we used a nickase Cas9 fused to adenosine deaminase to correct mutations in the radial spoke head component 4 A (RSPH4A) gene, causing PCD. We selected two PCD patients sharing the same SNV in RSPH4A, one with compound heterozygosity (child, patient 1) and one with homozygosity (adult, patient 2). After designing gRNAs, HEK293T cells with or without a DNA fragment containing the SNV in RSPH4A, were co-transfected with base editor plasmids. Complex formation and editing efficiency were validated by Western blot and digital PCR. We then treated patient cells with AAV containing the base editors and assessed ciliary beat frequency and motion pattern using high-speed video and confocal microscopy to evaluate delivery.Base editor complexes formed efficiently in vitro. AAV-mediated delivery in patient 1 cells led to an approximately 30.4% increase in normal motion pattern, with a corresponding reduction in circular motions (p < 0.001) compared with pre-treatment, and a 20% of editing efficiency detected by dPCR in transduced cells. Our data indicate that this limited editing efficiency is due to reduced AAV penetration in the lower layers of cells.This proof-of-concept study demonstrates the therapeutic potential of base editing for PCD, though current limitations include low editing efficiency and restricted delivery to inner cell layers in our experimental model. Future work should focus on optimizing base editors and testing novel delivery strategies to target progenitor cells, thereby enhancing the prospects for personalized gene therapy in PCD.
2026-02-27 | Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by defective motile cilia and impaired mucociliary clearance. Mutations in CCDC40 disrupt axonemal organization, resulting in dyskinetic or immotile cilia. While emerging therapies may restore function in only a subset of cells, the functional consequences of mixed populations of mutant and healthy cilia are not well understood. To determine how defined mixtures of CCDC40-deficient and wild-type ciliated cells influence mucociliary transport. Human bronchial epithelial cells were combined at varying ratios of CCDC40-deficient and wild-type cells and differentiated to model heterogeneous epithelia. High-speed video microscopy and particle-tracking algorithms were used to assess ciliary motion and mucus transport and combined with electron microscopy to evaluate cilia ultrastructure. Airway differentiation was largely preserved with marked ultrastructural defects observed in CCDC40 cells, including multiple central centrioles, absent inner dynein arms, and basal body misorientation. Ciliated surface coverage decreased, and goblet coverage increased with higher mutant representation. Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures. Clearance-per-beat and flow coordination decreased sharply with rising mutant burden. Modeling revealed that transport efficiency was equivalent to that recorded in ex vivo human tissues and plateaued when ~75% of the ciliated population was WT. Together, these findings define a PCD-specific functional correction threshold and show that effective therapy must overcome the disruptive biomechanical and cellular influences of mutant epithelial cells, providing a quantitative benchmark to guide gene-therapy design and clinical translation.
2026-02-06 | Compound heterozygous DAW1 variants reveal tissue-specific roles in left-right patterning and congenital heart disease without primary ciliary dyskinesia.
Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with HTX and complex congenital heart disease but no clinical signs of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1G>A) and a paternally inherited missense variant (c.341G>A; p.Arg114Gln), both classified as variants of uncertain significance under ACMG/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln fully rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1G>A as pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.
other
2025-05-01 | Antigen Stasis and Increased IL-33 Activation in the Human Primary Ciliary Dyskinesia Epithelium
Abstract Introduction. Antigen stasis on dysfunctional cilia leads to oxidative stress and DUOX1 activation in human primary ciliary dyskinesia (PCD) cells grown at air liquid interface (ALI) (PMID: 38318660). Activated DUOX-1 can increase epithelial activation of the alarmin IL-33, which binds to ST2 receptors (PMID: 27812543) on inflammatory cells, releasing cytokines associated with asthma. Recent publications suggest that a majority of patients with PCD may also have asthma. However, IL33 has not previously been studied in the PCD epithelium. Materials and methods. Primary nasal epithelial cell (normal HC – healthy control and PCD) grown to full ciliation at ALI included two biologic replicates from patients with PCD (genotypes DNAH11 and DNAH5) and from two healthy control (HC) subjects (all four are male). The ratio of cleaved (activated)/full length (CL/FL) IL-33 was measured in cell lysate and in the basolateral cell media four hours after a medium change. Immunoblot was carried out using the Jess (Protein Simple) 24 lane system and an optimized rabbit monoclonal antibody (E2TSL #88513; Cell Signaling). We also performed an ELISA assay (R/D Systems Cat # D3300B), comparing cellular to released IL33, in the presence and absence of the common asthma-associated antigen, Derp1. Results. By immunoblot, IL33 activation (CL/FL IL-33 ratio) was higher in PCD epithelial cell media than HC cells (p < 0.0001), but not in the cell lysates (Figure). Derp-1 treatment of PCD airway epithelial cells at ALI (3 technical replicates each) with or without Derp1 (active; 2 h) revealed that PCD cells release more activated IL33 after 4 hr Derp1 exposure than do baseline PCD cells or HC cells. (p < 0.05). Conclusions. Activation and release of the asthma-associated alarmin, IL33, is increased in primary human airway epithelial cells at ALI patients with PCD, an effect increased by apical antigen. It will be important to study the downstream immunology to ascertain whether this increased IL33 activation contributes to an asthma-like phenotype in patients with PCD. IL33 and downstream mediators may ultimately prove to be suitable targets for PCD treatment.
2024-08-17 | A 3000-year-old founder variant in the DRC1 gene causes primary ciliary dyskinesia in Japan and Korea.
Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by ciliary structural abnormalities and dysfunction, leading to chronic rhinosinusitis, otitis media with effusion, bronchiectasis, and infertility. Approximately half of Japanese PCD cases are attributed to variants in the dynein regulatory complex subunit 1 (DRC1) gene, predominantly featuring homogeneous deletions of exons 1-4 spanning 27,748 base pairs on chromosome 2. Here, we report 10 new PCD cases (9 families) in addition to 29 previously reported cases (24 families) caused by DRC1 variants. Among these 39 cases, biallelic DRC1 exon 1-4 deletions were detected in 38 (97.4%). These DRC1 deletions exhibited an identical breakpoint in all PCD cases in the Japanese and Korean populations, strongly suggesting a founder effect. In this study, we performed haplotype analysis, using a whole-exome sequencing dataset of 18 Japanese PCD patients harboring large biallelic DRC1 deletions. We estimated that the founder allele likely emerged 115.1 generations ago (95% confidence interval: 33.7-205.1), suggesting an origin of approximately 3050 years ago, coinciding with the transition from the Jomon period to the early Yayoi period in Japan. Considering the formation of the modern Japanese population, the founder with the DRC1 exon 1-4 deletion likely lived on the Korean peninsula, with the allele later transmitted to Japan through migration. This study provides insights into the origin of the DRC1 copy number variant, the most frequent PCD variant in the Japanese and Korean populations, highlighting the importance of understanding population-specific genetic variations in the context of human migration and disease prevalence.
2023-12-16 | Airway microbiota correlated with pulmonary exacerbation in primary ciliary dyskinesia patients.
PCD is a rare disease characterized by productive cough, rhinitis, and recurrent infections of the upper and lower airways. Because the diagnosis of PCD is often delayed, patients receive more antibiotics, experience a heavier financial burden, and have a worse prognosis; thus, it is very important to identify the pathogeny and use the correct antibiotic. In this large single-center study of PCD microbiota, we identified an outline of the bacterial microbes from the respiratory tract; furthermore, we found that the microbiota diversity in pediatric sputum was richer than that in pediatric BALF through sequencing, indicating a heterogeneous community structure. The microbiota diversity and richness were lower during pulmonary exacerbation than during pulmonary stabilization. A significantly higher abundance of Pseudomonas had a moderate distinguishing effect for lung exacerbation, which attracted more attention for the study of Pseudomonas therapy in pediatric patients with PCD.
2023-08-04 | RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis
A core pathophysiologic feature underlying many respiratory diseases is multiciliated cell dysfunction, leading to inadequate mucociliary clearance. Due to the prevalence and highly variable etiology of mucociliary dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in a complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelia, however this does not apply to all cell types, nor does it occur evenly across all cells in the same cell population. In this study we further investigated how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells, we identify RBL2 as a repressor of the transcriptional activity of Multicilin. Knockdown of RBL2 in submerged cultures or phosphorylation of RBL2 in response to apical air exposure, in the presence of Multicilin, allows multiciliogenesis to progress. These data demonstrate a dynamic interaction between RBL2 and Multicilin that regulates the capacity of cells to differentiate and multiciliate. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases with impaired mucociliary clearance.
2022-04-18 | Genes associated with situs inversus in patients with primary ciliary dyskinesia are identified by the weighted gene correlation network analysis
Abstract Background. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by immotile and dysmotile cilia or absence of cilia. Situs inversus (SI) is one of the phenomena frequently observed in PCD. However, little is known about the association between SI with PCD. Material and Methods. The microarray data of PCD were retrieved from the Gene Expression Omnibus (GEO) database to construct the co-expression network by the weighted gene co-expression network analysis (WGCNA). R software package Limma was used to perform the differential analysis. The gene network modules associated with SI screened with the common genes were further annotated based on Gene Ontology (GO) database and enriched based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Gene Set Enrichment Analysis (GSEA) was applied to identify the significant pathways. CIBERSORT was used to perform the correlation analysis of immune cells. The protein-protein interaction (PPI) network was constructed based on STRING database to identify the hub genes in the network. Results. Genes involved in PCD were identified related to SI. The results of the correlation analysis of immune cells showed that there were significant differences in the activated contents of dendritic cells. The WGCNA analysis revealed a total of 8 hub genes (i.e., ATP5A1, NDUFS3, NDUFV2, PSMC3, UBE2M, ALDH18A1, DBT, FOXRED1 ). Based on the GO annotations of hub genes, a group of GO terms were revealed to show significant difference, including mitochondrial part, oxidoreductase complex, cytosol, mitochondrial respiratory chain complex I, NADH dehydrogenase complex, respiratory chain complex I, catalytic complex, mitochondrial envelope, respiratory chain complex, and mitochondrial respiratory chain. KEGG enrichment analysis of hub genes identified a group of metabolic pathways showing significant difference, including Propanoate metabolism, beta-Alanine metabolism, Fatty acid degradation, Valine, leucine and isoleucine degradation, Huntington disease, Carbon metabolism, Fatty acid metabolism, Lysine degradation, Butanoate metabolism, and Metabolic pathways. Conclusion. Our study identified the variations in immune cells in PCD patients. The hub genes provide novel therapeutic targets for the diagnosis and treatment of PCD and SI.
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Drug Discovery Landscape
9 orphan drug designations for Primary ciliary dyskinesia.
9 orphan drug designations for Primary ciliary dyskinesia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
DNAI1 mRNA encapsulated in a selective organ targeting lipid nanoparticle | RNAs | FDA | ReCode Therapeutics, Inc. | |
mRNA encoding the ciliary protein CCDC40 | RNAs | FDA | — | Ethris GmbH |
Messenger ribonucleic acid coding for coiled-coil domain-containing protein 40 | RNAs | EMA | — | Ethris GmbH |
3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)-carbamimidoyl)pyrazine-2-carboxamide, Sodium chloride solution 4.2% (w/v) | small molecules | EMA | — | QbD Flanders |
3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl((2S,3R,4R, 5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)-carbamimidoyl)pyrazine-2-carboxamide | small molecules | FDA | Parion Sciences, Inc. | |
Cyclo[L-alanyl-L-seryl-L-isoleucyl-L-prolyl-L-prolyl-L-glutaminyl-L-lysyl-L-tyrosyl-D-prolyl-L-prolyl-(2S)-2-aminodecanoyl-L-alpha-glutamyl-L-threonyl]acetate salt | peptides | EMA | — | Santhera Pharmaceuticals (Deutschland) GmbH |
(R)-N-[2-(6-Chloro-methoxy-1H-indol-3yl)propyl]acetamide | — | FDA | — | Phase 2 Discovery, Inc. |
Tetrabenazine | — | FDA | Prestwick Pharmaceuticals, Inc. | |
Uridine 5'-triphosphate | small molecules | FDA | — | Inspire Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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