Novel compound may correct pathological airway mucus in cystic fibrosis [PreClinical]

1. Mucus from cystic fibrosis patients had a rope-like structure and high elasticity due to chemical cross-links between mucin proteins.

2. A compound designed to break down mucin cross-links was more effective in vitro than a currently available drug and was safe in mice.

Evidence Rating Level: 2 (Good)

Study Rundown: In lung diseases such as cystic fibrosis, pathological mucus is highly elastic and thus cannot be readily cleared from the airway. In this study, researchers identified the cause of the pathology and designed a chemical compound to improve mucus biophysical properties. Mucin proteins in cystic fibrosis sputum samples were rope-like and elastic as a consequence of disulfide cross-links, which formed under oxidative stress. The researchers tested two chemical compounds for their ability to break down such cross-links in sputum and decrease pathological elasticity: the mucolytic drug N-acetylcysteine (NAC) and the novel compound methyl 6-thio-6-deoxy-α-D-galactopyranoside (TDG). A low dose of TDG was more effective than that of NAC in decreasing mucus elasticity. In an initial test of TDG safety in mice, no significant toxicity was found.

This study provided the first evidence that the elastic property of cystic fibrosis mucus is caused by cross-links between mucin polymers that form under oxidative stress. Additionally, TDG has the potential to be an effective mucolytic drug that is more palatable than the currently available NAC, which has a characteristic rotten egg odor. Important next steps in the development of TDG as a therapeutic include testing for efficacy in an animal model of cystic fibrosis.

Click to read the study in Science Translational Medicine

Relevant Reading: Oxidants and the pathogenesis of lung diseases

In-Depth [in vitro study]: Sputum samples were collected from healthy and cystic fibrosis volunteer subjects. The elastic properties of the mucus were determined using a cone-and-plate rheometer. In brief, mucus was placed in between a metal plate and cone; as the plate and mucus were rotated, the force exerted by the mucus on the cone corresponded to mucus elasticity. The elastic modulus for cystic fibrosis mucus was higher than that for healthy mucus (p < 0.01).

Chemical measurements showed that while both types of mucus had similar levels of cysteine amino acids that have the potential to form disulfide bonds, cystic fibrosis mucus contained significantly more oxidized disulfide bonds (p < 0.01). Further, cystic fibrosis mucus contained significantly more neutrophil cells (p < 0.01) and their oxidative protein (p < 0.001). Separate experiments confirmed that oxidation directly caused mucin to form disulfide bonds.

TDG was designed to break mucin disulfide bonds via reduction, the opposite chemical process of oxidation. Chemical characterization of TDG showed that it had significantly more reducing activity than NAC (p < 0.01). In vitro, treatment of cystic fibrosis sputum with 10 mM of TDG resulted in a greater decrease in elastic modulus than treatment with 10 mM of NAC (p < 0.05). In a preliminary safety study, TDG and the sugar from which it was derived were administered intranasally to mice. Safety outcomes including body weight and immune cell count were not significantly different between the treatment groups. Variation between blood urea nitrogen as a measure of renal function was marginally significant between treatment groups (p = 0.046).

Image: PD

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