UNC lung researchers awarded $12.5-million NIH grant to develop new drug compounds

The National Institutes of Health has awarded four UNC experts a translational program project grant (tPPG) to develop and test therapeutics aimed at reducing the hyper-concentration of mucus often found in cystic fibrosis and asthma patients.

For patients with cystic fibrosis (CF), asthma, and other lung diseases, being able to clear mucus from their lungs can have an enormous impact on the quality of life. In CF, for example, mucus can become not just sticky but hyper-concentrated, which in turn makes breathing difficult by obstructing airways, exacerbating inflammation of the lung tissue, and increasing the risk of infection.

At the UNC School of Medicine, a diverse array of researchers at the Marsico Lung Institute (MLI) and the Center for Environmental Medicine, Asthma and Lung Biology (CEMALB) -- from biochemists to clinical physicians – are working to better understand the role mucus plays in lung diseases and find ways to target it therapeutically, making it easier for patients to clear this substance from their lungs. A five-year, $12.5-million grant renewal from the National Institutes of Health will help researchers at the MLI and CEMALB continue their important work.

Richard Boucher, MD, director of the Marsico Lung Institute, and David Peden, MD, director of the Center for Environmental Medicine, Asthma and Lung Biology, are co-principal investigators on the project.

Among the ways UNC researchers have previously attempted to improve clearance was through hydration with hypertonic saline solution, and while this was found to be effective in some cases, hydration therapy was also found to have its limits.

What was missing from hydration therapy was an effective mucolytic – a compound that makes mucus less thick, less sticky and easier to clear from the lungs. Research funded by the newest cycle of the grant will focus on two mucolytic agents – P2176 and P2114 – and try to better understand how these agents interact with the mucin proteins that contribute to the concentration and adherence of mucus in patients with CF and asthma.

The grant will support four interrelated projects:

  • An investigation of the roles of MUC5AC (an “asthma” mucin) and MUC5B (a “CF/COPD” mucin) as disease-specific targets, led by Michael Rubinstein, PhD, the John P. Barker Distinguished Professor of Chemistry in the UNC College of Arts and Sciences and member of the UNC Marsico Lung Institute.
  • A comparison of the two mucolytic agents in animal models to better understand the dose, dose frequency and the requirement for hypertonic saline as part of effective treatment, led by Boucher, who is also the James C. Moeser Eminent Professor of Medicine.
  • A clinical study of the safety and short-term efficacy of the mucolytic agents in CF populations, led by Scott Donaldson, MD, associate professor of medicine in the division of pulmonary diseases and critical care medicine and member of the UNC Marsico Lung Institute.
  • A clinical study of the safety and short-term efficacy of the mucolytic agents in asthma patients, led by Peden, who is also the Harry S. Andrews Distinguished Professor of Pediatrics and director of the UNC Institute for the Environment.

The goal of the grant is to use the work of this diverse group of researchers to advance an entirely new class of drug compounds for patients in need pulmonary mucus clearance, especially those with CF, asthma, and potentially chronic obstructive pulmonary disorder, which is the third leading cause of death in the U.S.

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