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
440 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:
440 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:
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.
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.
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.
2026-07-22 | 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.
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.
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.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
DNAI1 mRNA encapsulated in a selective organ targeting lipid nanoparticle | RNAs | FDA | 2024-06-25 | — | ReCode Therapeutics, Inc. |
mRNA encoding the ciliary protein CCDC40 | RNAs | FDA | 2023-09-26 | — | Ethris GmbH |
Messenger ribonucleic acid coding for coiled-coil domain-containing protein 40 | RNAs | EMA | 2023-07-25 | — | 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 | 2020-11-16 | — | 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 | 2020-05-05 | — | 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 | 2017-02-27 | — | Santhera Pharmaceuticals (Deutschland) GmbH |
(R)-N-[2-(6-Chloro-methoxy-1H-indol-3yl)propyl]acetamide | — | FDA | 2003-07-03 | — | Phase 2 Discovery, Inc. |
Tetrabenazine | — | FDA | 1998-05-12 | — | Prestwick Pharmaceuticals, Inc. |
Uridine 5'-triphosphate | small molecules | FDA | 1996-06-26 | — | Inspire Pharmaceuticals, Inc. |
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