Scientists have developed a revolutionary new treatment for COPD, asthma, and cystic fibrosis that mitigates the potentially deadly symptoms of the conditions.
The novel drug, developed by a multicenter research team co-led by The University of Texas MD Anderson Cancer Center, controls mucus secretion in the airways that cause symptoms of the conditions. The treatment for COPD, asthma, and cystic fibrosis also remedies lung disease caused by cancer and cancer treatment.
Burton Dickey, MD, professor of Pulmonary Medicine and co-corresponding author of the study, commented: “Mucus is a significant problem in pulmonary medicine because, in people with these common lung diseases, thick mucus can block the airways and cause symptoms ranging from a mild cough to very serious decreases in lung function. Most drugs for these conditions work to reduce inflammation or expand the airways to help people breathe better, but mucus is the most serious issue. Our research has created the first drug that would stop the secretion of mucins in its tracks.”
The research, published in Nature, was supported by the National Institutes of Health and the Cystic Fibrosis Foundation.
Dangers of Muco-obstructive lung diseases
Hundreds of millions of people are affected by muco-obstructive lung diseases globally, with 25 million people having asthma and 16 million adults diagnosed with COPD in the US alone. Moreover, cystic fibrosis is the most common life-threatening genetic disease. Cancer patients often develop lung disease due to their treatments, or cancer itself renders them immunocompromised.
Mucins are released gradually into the airways, absorbing water and forming a thin protective layer of mucus that traps pathogens and is cleared by cilia quickly. However, in muco-obstructive lung diseases, extremely high concentrations of mucins are released that are unable to absorb sufficient water, causing thick mucus that plugs airways and stops the lungs from functioning correctly.
The researchers have been investigating mucin secretion for 20 years and identified essential genes and proteins involved, finding that synaptotagmin and a SNARE complex are influential in the process of Ca2+-triggered membrane fusion.
Dickey said: “We built up a picture of what the secretory machinery looked like, and we knew all of the major players. Once we had an idea of how all the pieces worked together, we determined synaptotagmin-2 (Syt2) was the best protein to target to block mucin secretion because it only becomes activated with a high level of stimulation. Therefore, blocking the activity of Syt2 should prevent sudden massive mucin release without impairing slow, steady baseline mucin secretion that is required for airway health.”
Innovating lung medication
The team verified Syt2 as a promising therapeutic target protein in an array of preclinical models, from which they created a hydrocarbon-stapled peptide called SP9 to block it. Stapled peptides are a recent innovation that comprises modified amino acids that form hydrocarbon crossbridges that give it a robust structure to bind to a target protein.
Additionally, stapled peptides have been employed to treat a range of diseases, including cancer. However, SP9 is the first treatment for COPD, asthma, and cystic fibrosis that would be utilised as an inhaled therapeutic.
The researchers successfully used SP9 to disrupt Ca2+-triggered membrane fusion in a reconstitute system model and used SP9 conjugated to a cell-penetrating peptide in cultured epithelial cells to achieve rapid mucin secretion. Subsequently, the team used an aerosolised version of SP9 in a mouse model to validate the drug-reduced mucin secretion and airway blockage by the mucus, finding that the drug did not impact the slow-release pathway for normal mucin secretion.
“An inhaled drug like this could help someone during an acute attack of airway disease by stopping the rapid secretion of mucin and, by extension, avoiding the production of thick mucus. You can’t move air through an airway that’s plugged,” Dickey said. “In asthma, COPD and cystic fibrosis, it’s been shown that persistent plugs drive the most serious disease. Now we have a drug that could be very important if it’s shown to work in clinical trials.”
The potential treatment for COPD, asthma, and cystic fibrosis will now be refined before moving on to human studies and will possibly enter clinical trials in the next few years.
