Project 2 has focused on the hypotheses that: (1) hyperconcentrated (dehydrated) mucus produces airway mucus adhesion/plaques that drive the progression of muco-obstructive lung diseases; and, (2) that clearance of these plugs/plaques will be therapeutically useful in patients with the muco-obstructive phenotype. Recent data have indicated that once mucostasis has occurred, modification of mucus plaques may occur that make them ?permanent? and resistant to rehydration therapies. Our biophysical analyses suggest that mucin molecular weight (MW) reduction will be effective in clearing mucus in this setting without rehydration. Further, Project 2 hypothesizes that by the generation of disease specific models, that effectively mimic the extracellular mucins/mucus targets of our disease populations, will produce useful information to guide the clinical projects with respect to selection of drug doses, dosing frequency, requirement for an active vehicle (e.g., hypertonic saline) and generate data on ?off target? redox effects. In collaboration with tPPG investigators, we have established that in CF (and COPD) MUC5B is the dominant mucin obstructing airways. In contrast, we have identified that MUC5AC is the dominant airway mucin in subjects with asthma. Accordingly, we have generated appropriate cell culture, small animal, and sheep models that mimic the mucin dominance phenotype for each disease entity. Utilizing these tools, Project 2 will measure and compare the pharmacodynamics and pharmacokinetic properties of two different, but complementary, thiol reducing agent clinical candidates. P2176 is a di-thiol compound with rapid reductive activity (Kcat) whereas the mono-thiol P2114 has a slower intrinsic reductive (Kcat) activity. Both molecules share features designed to retain the molecules on the airway surface and both molecules have their thiols ?capped? by acetate groups that are cleaved by esterases on airway surfaces to liberate active compounds. The relative effectiveness/properties of each molecule will be tested in: (1) in vitro HBE cultures designed to mimic the extracellular MUC5AC/MUC5B ratios of CF/COPD (Il-1? treated) and asthma (IL-13 treated); (2) mouse models of CF/COPD (?ENaC) mice, and asthma (house dust mite treated) to measure clearance of mucus plugs after aerosol drug delivery; and, large animal sheep models, including wild-type, Ascaris suum exposed, and HNE/CF172 treated sheep to measure pharmacodynamics and pharmacokinetic parameters. Based on these data, and GLP toxicology studies, a lead molecule doses/dosing frequency, and a vehicle will be selected. Importantly, Project 2 will also utilize information gained from Project 1/Project 2 studies and clinical Projects 3 and 4 to study backup compounds as improvements in the frontrunner become identified/implemented in the parent thiol compound chassis. Thus the overarching goal of the 2b Project is to identify the optimal drug properties, balancing rate of mucin thiol reduction, duration of activity, and safety, to develop a new class of muco-clearance assisting agents that focus on mucin MW reduction that can be delivered alone or in combination with hydrating agents.
for Project 2 Muco-obstructive lung diseases constitute a major health burden to citizens of the United States. This Project aims to speed the development of novel and effective therapies to help patients in need clear disease causing secretion from their lungs.
| Abdullah, Lubna H; Coakley, Raymond; Webster, Megan J et al. (2018) Mucin Production and Hydration Responses to Mucopurulent Materials in Normal versus Cystic Fibrosis Airway Epithelia. Am J Respir Crit Care Med 197:481-491 |
| 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 |
| Jacobson, David R; McIntosh, Dustin B; Stevens, Mark J et al. (2017) Single-stranded nucleic acid elasticity arises from internal electrostatic tension. Proc Natl Acad Sci U S A 114:5095-5100 |
| Ge, Ting; Kalathi, Jagannathan T; Halverson, Jonathan D et al. (2017) Nanoparticle Motion in Entangled Melts of Linear and Nonconcatenated Ring Polymers. Macromolecules 50:1749-1754 |
| Zeman, Kirby L; Balcazar, Juan Rojas; Fuller, Fred et al. (2017) A Trans-Nasal Aerosol Delivery Device for Efficient Pulmonary Deposition. J Aerosol Med Pulm Drug Deliv 30:223-229 |
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