A multicenter research team led by the University of Texas MD Anderson Cancer Center has developed the first drug that can help people with asthma, COPD, cystic fibrosis, and lung disease caused by cancer and cancer treatment.
The drug works by preventing mucins from being released into the airways, which can cause potentially fatal symptoms in people with these conditions.
The research was published in Nature today.
“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,” says Burton Dickey, co-corresponding author of the study. “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.”
Hundreds of millions of people throughout the world suffer with mucosal obstructive lung disease. About 25 million people in the United States have asthma, 16 million adults have COPD, and CF is the most common life-threatening hereditary condition. Many cancer patients get lung disease as a result of their therapy or cancer itself, which has rendered them immunocompromised.
Mucins are normally released gradually into the airways, where they absorb water and produce a thin film of protective mucus that traps pathogens while being easily removed by cilia. When mucins are rapidly released in muco-obstructive lung illnesses, they are unable to absorb enough water, resulting in a thick mucus that can clog airways and impede lung function.
Dickey’s group has been studying mucin secretion for two decades and has already discovered the main genes and proteins involved, demonstrating how synaptotagmin and a SNARE complex, similar to that found in neurons, play a role in the critical process of Ca2+-triggered membrane fusion.
“We built up a picture of what the secretory machinery looked like and we knew all of the major players,” adds Dickey. “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.”
A number of preclinical models were used in this study to demonstrate that Syt2 is an effective therapeutic target protein.
Based on structures developed by Stanford collaborators, including senior co-corresponding author Axel Brunger, Ph.D., professor of Molecular and Cellular Physiology, Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of the Institute for Applied Cancer Science, designed a hydrocarbon-stapled peptide, SP9, to block Syt2.
Stapled peptides are a new therapeutic development that consists of modified amino acids that create hydrocarbon crossbridges to keep their structure tight so that they can attach to a protein target and demonstrate improved stability. SP9 would be the first stapled peptide to be utilized as an inhalation therapy. Stapled peptides have been used to treat various disorders, including cancer.
The Stanford laboratory of Ying Lai, Ph.D., used SP9 to successfully disrupt Ca2+-triggered membrane fusion in a reconstituted system model in Brunger’s laboratory. The Ulm lab of Manfred Frick, Ph.D., used SP9 bound to a cell-penetrating peptide in cultured epithelial cells to slow down the production of mucin. The Dickey team subsequently tested an aerosolized version of the medication in a mouse model to see if it reduced mucin secretion and mucus-induced airway obstruction. Importantly, SP9 had no effect on normal mucin secretion via the slow-release mechanism.
“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 production of thick mucus. You can’t move air through an airway that’s plugged,” explains Dickey. “In asthma, COPD and CF, 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.”
As with most therapeutics at this point in development, the stapled peptide SP9 will be reworked before going into human trials. It could start clinical trials in a few years.
Image Credit: Getty