Cystic fibrosis (CF)
lung disease is marked by high concentrations of
neutrophil elastase (NE) and
DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human
dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE
therapies for patients with CF. We investigated whether synthetic, low-molecular weight polysulfated
hyaluronan GlycoMira-1111 (GM-1111) would be effective as an anti-NE drug using ex vivo CF sputum. Anti-NE activity of GM-1111 was tested in CF sputum in the presence or absence of
dornase alfa and/or hypertonic saline using a spectrophotometric assay specific for human NE and was compared with
unfractionated heparin. We tested whether GM-1111 disaggregated
DNA from CF sputum (using gel electrophoresis analysis) or modified CF sputum viscoelastic properties (using a dynamic rheometer). GM-1111 and
unfractionated heparin had near equivalent anti-NE activity in CF sputum in the presence of
dornase alfa. Both GM-1111 and
unfractionated heparin retained anti-NE activity in hypertonic saline but with decreased activity. GM-1111 increased the release of soluble
DNA in CF sputum, resulting in improved depolymerization efficacy of
dornase alfa. GM-1111 decreased CF sputum elasticity. GM-1111 inhibited NE activity, enhanced
DNA depolymerization by
deoxyribonuclease, and decreased viscoelastic properties of CF sputum, similar to effects reported previously for
unfractionated heparin. Unlike heparins, GM-1111 is synthetic, with minimal
anticoagulant activity, and is not derived from animal products. These key attributes provide advantages over
unfractionated heparin as a potential therapeutic for CF.