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Future Research Directions in the Pathogenesis, Treatment, and Prevention of Early Cystic Fibrosis Lung Disease

Executive Summary

The twenty years since discovery of the gene encoding CFTR, there has been significant progress in understanding of CF genetics, the structure and function of CFTR, how mutations disrupt CFTR function, and the infection and inflammation that destroy the CF lung. Those years have also brought several new treatments and potential therapies. Yet despite this progress, understanding of the genesis and evolution of lung disease remain uncertain, and CF remains a lethal disease. These are challenging but exciting problems that lie at the heart of early CF lung disease.

Universal newborn screening in the United States represents an unprecedented opportunity for investigating CF clinical manifestations at a very early stage, monitoring the progress of the disease longitudinally, and intervening in productive ways. Technologies to elucidate features of CF physiology, disease biomarkers, and new animal models of the CF pulmonary phenotype are in place. These powerful new capabilities have positioned the field to address questions about basic and clinical CF in ways that were not possible even 12 months ago to prevent or mitigate disease progression. On September 21-22, 2010, the National Heart, Lung, and Blood Institute convened a working group of CF experts to review the progress and direction of CF research and from these discussions identify and prioritize the research opportunities that hold the most promise to provide new mechanistic insight into the genesis and evolution of early cystic fibrosis (CF) lung disease.

While the combination of infection and inflammation are well known to remodel and damage CF airways, the sequence of changes in these processes and critical mechanisms underlying the pathogenesis of airway disease in CF remain obscure and could inform on preventive and therapeutic strategies. How loss of CFTR function leads to goblet cell expansion in the surface epithelium, hyperplasia of submucosal glands, and abnormal mucus are not well understood; insight into these processes could suggest novel preventive and therapeutic approaches. There are many hypotheses about the events that impair airway host defense and predispose to infection with opportunistic pathogens, but which of the many factors play key roles has been difficult to discern. New assays of lung disease in humans and novel animal models could provide an opportunity to further elucidate the origin and progression of CF lung disease. Knowledge of pathogenesis may also identify useful new biomarkers and outcome measures.

There is an increasing appreciation of the complex microbial communities colonizing the CF respiratory tract. However, little is known about how various bacteria interact with each other and how combinations of bacteria interact with the host to create chronic intractable CF lung infections. Availability of potential new treatments may offer an opportunity to compare quantitative measures of changes in airway biology with changes in health outcomes and respiratory symptoms to identify relationships that could guide therapeutic development. Further knowledge of the pathogenesis of CF lung disease and the development of new treatments may also benefit from a systems biology approach that combines basic and clinical research focused on the pathogenesis of lung disease.

Recommendations

Priority Research Areas:

  1. Leverage newborn screening to elucidate the natural history and clinical manifestations of early CF lung disease as a way to prevent disease and mitigate disease progression. Early diagnosis should provide an unprecedented opportunity to develop a comprehensive data and specimen repository and integrative research approach to explore the relationship and contribution of a range of factors including genotype, genetic modifiers, aspiration, nutrition and growth, microbiology (bacteria, viral, others?), inflammation, remodeling, etc. to disease pathogenesis and outcome and the role of CFTR in driving early stage disease.
  2. Explore mechanisms of early CF lung disease using existing and recently developed animal models (mice, pigs, and ferrets) including cross-species comparisons to humans to dissect the order of early pathologic events in the onset and progression of disease and make better informed directional connections between defects in airway clearance, innate immunity, and inflammation.
  3. Determine the role of mutant CFTR in airway growth (and development) and how it impacts on physiologic measures of lung function and the intersection of lung growth and inflammation.
  4. Develop a spectrum of biomarkers (including non-invasive markers) of early CF lung disease onset and progression targeting rate-limiting steps, downstream effects of CF pathophysiology, and response to treatment. These biomarkers should be suitable for use in infants and young children and link to clinically meaningful outcomes and be suitable to demonstrate a response to therapeutic intervention. These measures might include radiologic (or other imaging) measures of structural lung disease in concert with measures of physiologic function at the macroscopic level.
  5. Determine the mechanisms underlying early CF (and other) lung disease heterogeneity.
  6. Explore the role of CF modifier genes and their associated variants (identified by GWAS) in CF disease pathogenesis and disease outcome using integrative approaches with a focus on drugable targets and development of potential pharmacologic interventions into these pathways.
  7. Develop enabling technologies/tools/animal models of lung disease that are viable long term and allow examination of early CF lung pathogenesis onset and progression.

Working Group Members

Co-Chairs

  • Michael Welsh, M.D., University of Iowa
  • Bonnie Ramsey, M.D., University of Washington

Members

Group Leaders:

  • Group 1, Eric Sorcher, M.D., University of Alabama, Birmingham
  • Group 2, John Engelhardt, Ph.D., University of Iowa
  • Group 3, Pradeep Singh, M.D., University of Washington
  • Group 4, Christopher Karp, M.D., Children’s Hospital Medical Center, Cincinnati
  • Group 5, Garry Cutting, M.D., Johns Hopkins University
  • Group 6, Richard Boucher, M.D., University of North Carolina, Chapel Hill

Group Members:

  • Frank Accurso, M.D., University of Colorado (groups 1, 4, and 6)
  • William Guggino, Ph.D., Johns Hopkins University (groups 2 and 6)
  • Michael Knowles, M.D., University of North Carolina, Chapel Hill (group 5)
  • Jay Kolls, M.D., Louisiana State University Health Science center (groups 4 and 5)
  • John Lipuma, M.D., University of Michigan (group 3)
  • Susan Lynch, Ph.D., University of California, San Francisco (group 3)
  • Paul McCray, M.D., University of Iowa (groups 4 and 5)
  • Ronald Rubenstein, M.D., Ph.D., Children’s Hospital of Philadelphia (groups 1, 2, and 6)

NHLBI Staff

  • Susan Banks-Schlegel, Ph.D., Division of Lung Diseases
  • James P. Kiley, Ph.D., Division of Lung Diseases

Cystic Fibrosis Foundation Staff/Consultants

  • Drucy Borowitz, M.D., State University of New York at Buffalo
  • Christopher Penland, Ph.D., Cystic Fibrosis Foundation
  • Steven Rowe, M.D., MSPH, University of Birmingham, Alabama

Last Updated: November 2010

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