The overarching therapeutic goal for the UNC tPPG renewal is to clear the hyperconcentrated, adherent mucus that promotes airways obstruction, inflammation, and infection. A straightforward approach to treat muco-obstructive diseases is to rehydrate airway surfaces. However, recent experimental and biophysical analyses have identified that thickened adherent mucus can be modified to generate ?permanent? gels resistant to clearance by hydration. The therapeutic strategy identified to clear permanent mucus gels is the reduction mucin molecular weight (MW). Consequently, the tPPG is configured to take advantage of novel thiol mucin MW reducing agents, e.g., a di-thiol P2176 and a monothiol P2114, and has assembled a full drug development team to quickly and safely bring these molecules into patient populations in need. The tPPG will be overseen by a decision making Project Development/Statistical Core (Core A, Richard C. Boucher, MD, PI) that will guide selection and development of thiol class compounds and oversee selection of drug dose, dosing frequency, drug formulation and clinical trial designs. Projects/Cores overseen include: Project 1 (Michael Rubinstein, PhD., PI: Mechanism of Action of Mucolytics in Improving Mucus Clearance in Lung Disease), will focus on the relative roles of MUC5AC (an ?asthma? mucin) vs. MUC5B (a ?CF/COPD? mucin) as disease specific targets and generate biophysical measurements to assist in compound selection and as biophysical assays for the clinic. Project 2 (Richard C. Boucher, MD, PI: PK/PD Requirements for Mucolytic Therapeutic Agents In Vitro and In Vivo), will utilize in vitro, small animal, and large animal models to compare P2176 with P2114 with respect to mucolytic dose, dosing frequency, and the requirement for a hypertonic saline (HS) formulation. Project 3 (Scott Donaldson, MD, PI: Treatment of Mucostasis and Airways Obstruction in Cystic Fibrosis with a Novel Mucolytic), will test the safety and short term efficacy of P2176/P2114 in CF populations. Project 4 (David Peden, MD, PI: Treatment of Mucostasis and Airways Obstruction in Asthma with a Novel Mucolytic), will test on the safety and short-term efficacy of P2176/P2114 in patients with asthma under basal and allergen challenged conditions. The projects will be supported by three cores: (1) Core B, Analytics for Mucolytics (Mehmet Kesimer, PhD, PI), will provide a broad spectrum of biophysical and biochemical measurements of mucolysis; (2) Core C, In-vivo Imaging of Mucus Obstruction and Clearance (William Bennett, PhD, PI) will provide imaging of subjects, including radio-nuclide mucociliary clearance measurements and F19-MR ventilation imaging; and, (3) Core D, The Pharmacokinetics/Pharmacodynamics (Charles Esther, MD, PhD, PI) will provide measurements of pharmacodynamic and drug pharmacokinetic measurements of thiol compounds. The tPPG deliverable is to mobilize our experienced drug development group to advance a novel class of IND-ready therapeutic compounds into patients in need of pulmonary mucus clearance, including, asthma, CF, ultimately COPD.
- Overall Muco-obstructive lung diseases, including asthma, CF, and COPD constitute major health burdens to citizens of the United States. This tPPG aims to develop new and effective therapies to help patients in need of treatment for these diseases.
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| Yu, Dongfang; Saini, Yogesh; Chen, Gang et al. (2018) Loss of ? Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice. Am J Pathol 188:95-110 |
| Muhlebach, Marianne S; Hatch, Joseph E; Einarsson, Gisli G et al. (2018) Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 52: |
| Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S et al. (2018) Lung disease phenotypes caused by overexpression of combinations of ?-, ?-, and ?-subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol 314:L318-L331 |
| Chen, Gang; Volmer, Allison S; Wilkinson, Kristen J et al. (2018) Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice. Am J Respir Cell Mol Biol 59:383-396 |
| Bennett, William D; Zeman, Kirby L; Laube, Beth L et al. (2018) Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis. J Aerosol Med Pulm Drug Deliv 31:204-211 |
| Ge, Ting; Grest, Gary S; Rubinstein, Michael (2018) Nanorheology of Entangled Polymer Melts. Phys Rev Lett 120:057801 |
| Esther Jr, Charles R; Hill, David B; Button, Brian et al. (2017) Sialic acid-to-urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol 312:L398-L404 |
| Kesimer, Mehmet; Ford, Amina A; Ceppe, Agathe et al. (2017) Airway Mucin Concentration as a Marker of Chronic Bronchitis. N Engl J Med 377:911-922 |
| Wagner, Caroline E; Turner, Bradley S; Rubinstein, Michael et al. (2017) A Rheological Study of the Association and Dynamics of MUC5AC Gels. Biomacromolecules 18:3654-3664 |
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