Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease

Status Recruiting

Clinical Trial Summary

The overall short-term goals of this project include the following: 1) identify the genes that are key to the function of respiratory cilia to protect the normal lung; and 2) the effects of genetic mutations that adversely affect ciliary function and cause primary ciliary dyskinesia (PCD), which results in life-shortening lung disease. The long-term goal of this project is to develop better understanding of the underlying genetic variability that adversely modifies ciliary function, and predisposes to common airway diseases, such as asthma and chronic obstructive pulmonary disease.

Clinical Trial Description

A key component of lung defense is the efficiency of mucociliary clearance (MCC). Primary ciliary dyskinesia (PCD) is a human genetic disorder with defective MCC. This ongoing project is designed to identify additional disease-causing mutations in PCD, and correlate the molecular etiologies with the ciliary phenotype (ultrastructure, wave form and beat frequency). We have recently shown that the normal human cilium has a distinctive waveform, i.e. beats in-plane with defined curvatures and amplitudes for the effective (forward) and recovery stroke. We hypothesize that discrete sets of genes contribute to the structure and function of the ciliary outer dynein arm (ODA), inner dynein arm (IDA), and central pair (CP) and radial spoke (RS) complex (CP/RS), and that we can identify novel genetic mutations in different structural components of the cilium that will have different effects on ciliary ultrastructure, wave form, and beat frequency. Importantly, we are now able to identify patients with PCD who do not have hallmark diagnostic ultrastructural defects, based on distinctive clinical phenotypes (including situs inversus), low or borderline nasal NO production, and abnormal ciliary motility. Identification of PCD patients with normal ciliary ultrastructure (~16% of PCD patients at UNC) offers the opportunity to discover mutations in genes that cause functional, but not ultrastructural, defects (such as DNAH11), and to correlate those mutations with ciliary waveform abnormalities. Over the past 4 years, we have made great progress in identifying mutations in 2 genes (DNAI1 and DNAH5) that cause ~60% of ODA defects in PCD, and ~35% of PCD overall. We will extend our search for disease causing mutations in PCD, using several different approaches, including studies of additional candidate genes, (guided by ultrastructure), plus insights from ciliary proteomics, and family-based studies. Taken together, these studies will provide new insights regarding the relationship of mutations in specific genes to ciliary ultrastructural and functional defects. These studies will not only greatly enhance our ability to diagnose PCD, but will also lead to discovery of "milder" genetic mutations associated with normal ciliary ultrastructure, and likely some residual ciliary function. Ultimately, this will allow future studies of the role of partial loss of ciliary function in the predisposition to more common airways diseases, such as chronic bronchitis and chronic obstructive pulmonary disease. ;

Study Design

Related Conditions & MeSH terms

Clinical Trial Details

NCT number	NCT00807482
Study type	Observational
Source	University of North Carolina, Chapel Hill
Contact
Status	Recruiting
Phase
Start date	January 2004
Completion date	April 2025

View Details

See also
Status	Clinical Trial	Phase
Completed	`NCT00323167` - Rare Genetic Disorders of the Breathing Airways
Completed	`NCT03832491` - Effect of Game Based Approach on Oxygenation, Functional Capacity and Quality of Life in Primary Ciliary Dyskinesia	N/A
Recruiting	`NCT05161858` - Longitudinal Characterization of Respiratory Tract Exacerbations and Treatment Responses in Primary Ciliary Dyskinesia
Recruiting	`NCT04611516` - The Ear-Nose-Throat (ENT) Prospective International Cohort of PCD Patients (EPIC-PCD)
Recruiting	`NCT04919018` - Characterizing the Upper Airway Manifestations in Primary Ciliary Dyskinesia and Primary Immunodeficiencies
Completed	`NCT00722878` - Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
Completed	`NCT00608556` - Dyskinesia, Heterotaxy and Congenital Heart Disease	N/A
Completed	`NCT05040607` - Physical Fitness, Exercise Capacity and Activities of Daily Living in Primary Ciliary Dyskinesia: a Retrospective Study
Recruiting	`NCT03606200` - Swiss Primary Ciliary Dyskinesia Registry
Recruiting	`NCT03517865` - International Primary Ciliary Dyskinesia Cohort
Completed	`NCT00783887` - Diagnosis of Primary Ciliary Dyskinesia	N/A
Completed	`NCT02389049` - Genetics of Primary Ciliary Dyskinesia
Recruiting	`NCT04702243` - Defining the Genetic Etiology of Suppurative Lung Disease in Children and Adults

Clinical trials are conducted in a series of steps, called phases - each phase is designed to answer a separate research question.

Phase 1: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
Phase 2: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
Phase 3: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
Phase 4: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.