Current and Future Treatments in Primary Ciliary Dyskinesia

Paff, Tamara; Omran, Heymut; Nielsen, Kim G.; Haarman, Eric G.

doi:10.3390/ijms22189834

Cited by 63 publications

(61 citation statements)

References 113 publications

(136 reference statements)

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“…Azithromycin is currently widely used in chronic respiratory diseases including PCD (17), due to its ability to alleviate both infection and inflammation. More specifically, AZM plays an anti-infective role by inhibiting synthesis of bacterial proteins that can interfere with bacterial biofilm generation and production of other virulence factors (18). Concurrently, AZM plays an anti-inflammatory role by inhibiting host production of IL-8 and tumor necrosis factor-α (TNF-α) (19,20).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Azithromycin Treatment in Pediatric Primary Ciliary Dyskinesia: A Retrospective Study

et al. 2022

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ObjectivesPrimary ciliary dyskinesia (PCD) is a rare genetic disease mainly involved in lung dysfunction. PCD patient outcomes after azithromycin (AZM) treatment have rarely been reported. This study was aimed to assess AZM treatment effects on disease progression of pediatric PCD patients.Study DesignThis retrospective follow-up study involved PCD patients diagnosed from 2009 to 2021. Changes of clinical outcomes, pulmonary function, and chest computed tomography findings were compared between untreated and AZM-treated patients.ResultsOf 71 enrolled patients (median follow-up duration of 3.1 years), 34 received AZM (AZM-treated group) and 37 received no AZM (AZM-untreated group). At diagnosis, no significant intergroup differences in age, sex, height, weight, number of respiratory exacerbations, and FEV1% and FVC% predicted values were found, although FEF25–75% predicted was lower in AZM-treated group. Between treatment initiation and follow-up, patients in AZM-treated group had less respiratory exacerbations than that of AZM-untreated group (mean ± SD, 1.4 ± 0.8 vs. 3.0 ± 2.1, times/year P = 0.001) and fewer AZM-treated group patients exhibited exercise intolerance. Increases above baseline of AZM-treated FEV1% and FVC% predicted values exceeded that of AZM-untreated group, but intergroup differences were insignificant (FEV1% predicted: (median, IQR) 5.3 [−13.4, 9.4] vs. 1.8 [−12.1, 9.5], P = 0.477; FVC% predicted: (median, IQR) 6.7 [−7.6, 18.8] vs. 1.6 [−5.6, 7.6], P = 0.328).ConclusionLong-term AZM treatment can reduce respiratory infection frequency and may maintain pulmonary diseases stable in pediatric PCD patients with worse lung function.

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Section: Discussionmentioning

confidence: 99%

Long-Term Azithromycin Treatment in Pediatric Primary Ciliary Dyskinesia: A Retrospective Study

et al. 2022

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“…So far, three studies (ex vivo human or animal cell cultures) have been published describing the partial restoration of ciliary function in ciliopathies using classical gene therapy (Chhin et al, 2009; Ostrowski et al, 2014) and one study using gene editing (Lai et al, 2016). Further review of this interesting research area is outside the scope of this publication but can be sought in a recent review (Paff, Omran, Nielsen, & Haarman, 2021).…”

Section: Treatment With and Without Evidence—challenges And Future Po...mentioning

confidence: 99%

“…Nonsense mutations resulting in a premature termination codon (PTC) and thus translation into nonfunctional protein have been identified as disease causing in approximately one third of patients with PCD (Paff et al, 2018). Currently, in vitro studies on PTC therapeutics for PCD are being performed by Eloxx Pharmaceuticals (Waltham, United States of America (https://www.eloxxpharma.com/ accessed 8 Feb 2022), in collaboration with Amsterdam University Medical Center (The Netherlands) and University Medical Center Utrecht (The Netherlands) (Paff et al, 2021).…”

Section: Treatment With and Without Evidence—challenges And Future Po...mentioning

confidence: 99%

Chronic airway disease in primary ciliary dyskinesia—spiced with geno–phenotype associations

Nielsen

Holgersen

Crowley

et al. 2022

American J of Med Genetics Pt C

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Primary ciliary dyskinesia (PCD) can be defined as a multiorgan ciliopathy with a dominant element of chronic airway disease affecting the nose, sinuses, middle ear, and in particular, the lower airways. Although most patients with PCD are diagnosed during preschool years, it is obvious that the chronic lung disease starts its course already from birth. The many faces of the clinical picture change, as does lung function, structural lung damage, the burden of infection, and of treatment throughout life. A markedly severe neutrophil inflammation in the respiratory tract seems pervasive and is only to a minimal extent ameliorated by a treatment strategy, which is predominantly aimed at bacterial infections. An ever-increasing understanding of the different aspects, their interrelationships, and possible different age courses conditioned by the underlying genotype is the focus of much attention. The future is likely to offer personalized medicine in the form of mRNA therapy, but to that end, it is of utmost importance that all patients with PCD be carefully characterized and given a genetic diagnosis. In this narrative review, we have concentrated on lower airways and summarized the current understanding of the chronic airway disease in this motile ciliopathy. In addition, we highlight the challenges, gaps, and opportunities in PCD lung disease research.

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“…There are no specific treatments for PCD. Instead, PCD is managed with symptom-directed care based in expert opinion and extrapolation from other disease processes that have obstructive physiology such as cystic fibrosis [ 120 , 161 ]. Likewise, treatments for adults and children are extrapolated to address problems in the newborn.…”

Section: Evaluation and Management Of The Newborn With Suspected Pcdmentioning

confidence: 99%

“…Studies on the impact of disease on quality of life unfortunately show significant burden to affected individuals, which may be partially mitigated by early care [ 172 ]. Therapies to restore cilia function are under investigation with potential for success [ 161 ].…”

Section: Evaluation and Management Of The Newborn With Suspected Pcdmentioning

confidence: 99%

Impact of Motile Ciliopathies on Human Development and Clinical Consequences in the Newborn

Hyland

Brody

2021

Cells

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Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods they have essential roles in airway clearance in the respiratory tract and regulating cerebral spinal fluid flow in the brain. Dysregulation of motile cilia is best understood through the lens of the genetic disorder primary ciliary dyskinesia (PCD). PCD encompasses all genetic motile ciliopathies resulting from over 60 known genetic mutations and has a unique but often underrecognized neonatal presentation. Neonatal respiratory distress is now known to occur in the majority of patients with PCD, laterality defects are common, and very rarely brain ventricle enlargement occurs. The developmental function of motile cilia and the effect and pathophysiology of motile ciliopathies are incompletely understood in humans. In this review, we will examine the current understanding of the role of motile cilia in human development and clinical considerations when assessing the newborn for suspected motile ciliopathies.

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Current and Future Treatments in Primary Ciliary Dyskinesia

Cited by 63 publications

References 113 publications

Long-Term Azithromycin Treatment in Pediatric Primary Ciliary Dyskinesia: A Retrospective Study

Long-Term Azithromycin Treatment in Pediatric Primary Ciliary Dyskinesia: A Retrospective Study

Chronic airway disease in primary ciliary dyskinesia—spiced with geno–phenotype associations

Impact of Motile Ciliopathies on Human Development and Clinical Consequences in the Newborn

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