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Consortium Spotlight: Advancing Discoveries in Mucociliary Clearance Diseases

March 11 2022

The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) is a network of experts working together to better understand rare and genetic conditions leading to impairments in lung defenses and suppurative respiratory disorders, including primary ciliary dyskinesia, cystic fibrosis, primary immunodeficiencies, and idiopathic bronchiectasis. Here, principal investigators Stephanie Davis, MD, and Thomas Ferkol, MD, share the history of the consortium, current research, and future plans.

What are the overall goals of the GDMCC?

The human lung is exposed daily to inhaled pathogens, and innate host defenses and clearance mechanisms are critical in preventing acute and chronic pulmonary infections. However, the airway defenses are breached early in the lives of patients who have inherited immunodeficiencies or defective mucociliary clearance, which leads to chronic suppurative respiratory diseases and bronchiectasis.

Historically, bronchiectasis was often secondary to severe infection. Following the introduction and widespread use of antibiotics and immunizations, its incidence fell. In most North American and European populations, genetic diseases like cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiencies are now the most common causes of bronchiectasis.

The overarching goal of the GDMCC is to define the genetic bases, pathophysiology, and clinical course of rare, chronic, suppurative respiratory diseases, improve diagnostic capabilities, and identify novel therapeutic targets and endpoints for clinical trials that will ultimately improve outcomes for affected individuals.

How did the GDMCC team come together, and how did you become a part of the RDCRN?

Led by Michael Knowles, MD, and Margaret Leigh, MD, of the University of North Carolina-Chapel Hill, the GDMCC has been a member of the RDCRN since its inception. Beginning at four sites (University of North Carolina, Washington University in St. Louis, University of Colorado, and University of Washington), the consortium has expanded to eight clinical research sites from across North America.

When the GDMCC was created, little was known about the genetics, pathogenesis, and clinical spectrum of primary ciliary dyskinesia, but we have seen remarkable advances in our understanding of primary ciliary dyskinesia during the past 18 years.

The consortium has enrolled over 1,100 individuals with clinical suspicion for primary ciliary dyskinesia in a number of protocols that have evaluated genetics, ciliary ultrastructure, diagnostic tools, and clinical data. For instance, using next-generation and whole exome sequencing, the consortium has partnered with our European colleagues to identify genes implicated in primary ciliary dyskinesia, and our investigators have been involved in the discovery of most of the over 50 disease-associated genes. Through these studies, the consortium has also made new insights into diagnostics, which have led to several new, fundamental questions concerning the pathophysiology and disease progression in primary ciliary dyskinesia.

Can you tell us more about the rare diseases you study?

Primary ciliary dyskinesia is a rare, genetically heterogeneous disease, and mutations in proteins involved in cilia assembly, structure, or function can cause disease. Chronic sinopulmonary disease, persistent middle ear effusions, left-right laterality defects, and subfertility are common clinical manifestations. The reported prevalence in the general population is roughly 1 in 7,500 live births, but in children with repeated respiratory infections it has been estimated to be as high as 5%.

The focus of the consortium has evolved. In addition to primary ciliary dyskinesia, we initially studied several inherited and acquired disorders that lead to chronic suppurative respiratory diseases, including atypical cystic fibrosis, idiopathic bronchiectasis, and chronic airway infection with non-tuberculous mycobacteria. More recently, we are characterizing chronic suppurative respiratory disease caused by novel primary immunodeficiencies, conditions that can clinically overlap with primary ciliary dyskinesia.

What are your current research projects?

During this grant cycle, the consortium has three projects:

Project 5906, Cross-sectional study defining the genetic bases of non-cystic fibrosis suppurative lung diseases and bronchiectasis, focusing on primary ciliary dyskinesia and primary immunodeficiencies

Led by Michael Knowles, MD, and Kenneth Olivier, MD, MPH, this project is systematically characterizing the clinical phenotype and laboratory profile of patients with chronic suppurative respiratory diseases that are typically referred to pediatric and adult pulmonologists. The study design will test the hypothesis that systematic diagnostic evaluation at the eight consortium sites, coupled to genetic testing, will define the molecular diagnosis in the majority of patients with suppurative respiratory disease, including those with primary immunodeficiencies, primary ciliary dyskinesia, or another genetic disorder that interferes with airway defenses.

Project 5907, Longitudinal study assessing the effect of respiratory exacerbations on quality of life and disease progression in primary ciliary dyskinesia

This project is a longitudinal study driven by Margaret Rosenfeld, MD, MPH, and Scott Sagel, MD, PhD, that will examine respiratory tract exacerbations in primary ciliary dyskinesia. Respiratory tract exacerbations cause significant morbidity and substantial health care utilization, school and work absenteeism, and given their negative impact, they are obvious targets for interventional trials designed to establish evidence-based guidelines for their prevention and treatment. The overall objective of this project is to provide critical data needed to inform the design of future interventional trials of respiratory tract exacerbations prevention and treatment in children and adults with primary ciliary dyskinesia, including the use of innovative mobile health monitoring tools.

Project 5908, Cross-sectional study examining and comparing the clinical impact of the otolaryngological manifestations of primary ciliary dyskinesia and primary immunodeficiencies

Working with Adam Kimple, MD, PhD, and site otolaryngologists, this project is designed to comprehensively define and compare the clinical manifestations and morbidity of upper airway involvement in these diseases and determine whether specific genetic defects segregate into clinical subtypes that are associated with differing severities of sinonasal and middle ear disease.

How has your research impacted patients?

The consortium has made numerous advances that have profoundly changed diagnostic testing and clinical practice during the past 18 years, bringing bedside to the bench and back again. Systematic study of enrolled subjects with suppurative respiratory disease revealed a characteristic clinical phenotype for primary ciliary dyskinesia, consisting of four clinical features that largely distinguishes it from other respiratory conditions of childhood. These features are unexplained neonatal respiratory distress in term infants; early onset, year-round wet cough; early onset nasal congestion; and laterality defect.

We have tested and validated diagnostic tools, such as nasal nitric oxide measurements, and created clinical guidelines for the diagnosis of primary ciliary dyskinesia. Our gene discovery efforts have made genetic testing possible and is now considered a first-line diagnostic test for primary ciliary dyskinesia, incorporated into published diagnostic algorithms. The consortium has also found motile ciliopathies in other conditions, including congenital heart diseases, heterotaxy, hydrocephalus, and cri du chat syndrome.

The consortium has a long-standing partnership with the PCD Foundation. Perhaps the most direct impact of our work has been the creation and ongoing expansion of the PCD Foundation Clinical and Research Centers Network (CRCN) across North America. These sites are trained to diagnose primary ciliary dyskinesia, provide evidence-based clinical care, and potentially increase the pool of research participants for future clinical trials. Collaborating with the consortium, the PCD Foundation has also developed a sustainable clinical registry that captures natural history data on well-characterized patients seen at accredited clinical centers.

Finally, with our recent renewal, the consortium has collaborated with the Immune Deficiency Foundation, which has been a wonderful partnership given the phenotypic overlap between primary ciliary dyskinesia and many primary immunodeficiencies.

How has being part of the RDCRN impacted the GDMCC’s work?

It was vital. Without network support to provide the needed organization and infrastructure, none of the advances described above would have been possible.

How do you envision that the diseases you study can ultimately be cured?

While our understanding of primary ciliary dyskinesia has advanced, this knowledge has not been translated into treatment. There are only two randomized controlled trials of any treatment for primary ciliary dyskinesia described in the literature.

At present, no specific therapies are available to correct ciliary dysfunction at the cellular level. Such therapies remain in the pre-clinical phase. Nevertheless, there is potential for genetic therapies, such as mRNA, to ameliorate primary ciliary dyskinesia by restoring functional protein expression in cilia, and several biotechnology companies are exploring their use.

The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). GDMCC is funded under grant number U54HL096458 as a collaboration between NCATS and the National Heart, Lung, and Blood Institute (NHLBI).

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