University of Pittsburgh researchers have developed a novel Notch-dependent way to restore ciliary robustness in the airway that could lessen ongoing lung damage from these chronic diseases.
Cilia growth with DAPT (right) is improved three-fold over the control group (left) in human nasal tissue.
Description
In the lining of the airway, hair-like cilia sweep away foreign matter, microbial contaminants, and mucus. This clearance action is necessary for healthy lung function. Smoking, aging, and genetic mutations can compromise cilia action in the airway, leading to common respiratory illnesses, such as chronic obstructive pulmonary disease (COPD) and asthma, which together affect about 500 million people worldwide.
Researchers found that inhibiting Notch, the transcription factor responsible for transforming epithelial cells into mesenchymal cells, can restore ciliation and cilia function. By pushing the balance toward ciliated epithelial tissue, a Notch-inhibitor such as DAPT may improve lung clearance. Further, the ability of DAPT to improve lung function may prove helpful in the fight against COVID-19.
Applications
• Treating lung diseases such as COPD, primary ciliary dyskinesia, asthma, emphysema, cystic fibrosis, and hydrocephalus.
• Treating the life-threatening pneumonia that can result from COVID-19 infection.
Advantages
• Entirely novel way of treating common respiratory diseases.
• Potential therapeutic benefits in any body system in which cilia play a role, e.g. treating hydrocephalus—retention of fluid in the ventricles of the brain—by increasing cilia action to help with drainage.
Invention Readiness
In ex vivo experiments with mouse tracheal tissue, DAPT increased the number, length, and beat frequency of cilia three-fold. Inhibiting Notch signaling by inhibiting gamma secretase with DAPT enhanced the percentage of ciliation, and resulted in longer cilia that beat with higher frequency in both mouse and human airway epithelia.
IP Status
https://patents.google.com/patent/US20190336563A1Related Publication(s)
Zahid, M., Feinstein, T. N., Oro, A., Schwartz, M., Lee, A. D., & Lo, C. W. (2020). Rapid Ex-Vivo Ciliogenesis and Dose-Dependent Effect of Notch Inhibition on Ciliogenesis of Respiratory Epithelia. Biomolecules, 10(8), 1182. https://doi.org/10.3390/biom10081182
