Three promising experimental therapies target mucus plugs in severe asthma

Blessing Azeke pulled her sweater tighter as another asthma attack seized her lungs. She was sitting in her law school classroom in Enugu, Nigeria, when the cold air from the ceiling fan triggered the familiar constriction. Her airways tightened. Her breathing became shallow, then desperate. She could barely move. Within hours, she was in the faculty clinic again—her tenth emergency visit in just six months of law school.

Azeke's struggle is shared by more than 260 million people worldwide who live with asthma. For them, the disease is not a minor inconvenience but a constant threat. Cold air, allergens, dust, pollution—any of these can spark inflammation deep in the lungs, narrowing the airways and triggering a cascade of mucus production. The body's attempt to protect itself becomes the problem. Thick, sticky mucus accumulates, forming plugs that can completely block the smallest airways. These blockages are responsible for nearly half a million deaths each year.

The frustration for patients and doctors alike is that current treatments address only part of the problem. Anti-inflammatory drugs like corticosteroids reduce swelling and inflammation in the airways, but they do nothing to prevent the excessive mucus secretion or dissolve the plugs already clogging the lungs. Medications designed to clear mucus work on that front but fail to reduce inflammation or stop the body from producing more mucus. It is as if doctors have two separate toolkits, and neither one solves the whole puzzle.

Now, researchers are working on three distinct experimental approaches that could change this equation. At the heart of each strategy is a deeper understanding of what mucus actually is and why it becomes so problematic in asthma. Mucus is a complex mixture of water, dead cells, salt, fats, and proteins. Its primary structural component is a family of proteins called mucins, which give mucus its thick, gel-like consistency. In people with asthma, genetic changes in these mucin proteins make the mucus thicker and far harder to clear from the lungs. The thicker the mucus, the more easily it accumulates into dangerous plugs.

One research team, led by Christopher Evans at the University of Colorado's Anschutz Medical Campus, is pursuing a mucolytic approach—drugs that break apart the chemical bonds holding mucin proteins together. In laboratory studies, Evans and his colleagues exposed mice to a fungal allergen once weekly for four weeks, triggering inflammation and mucus overproduction that mimicked an asthma attack. They then treated the mice with an experimental mucolytic agent called tris(2-carboxyethyl)phosphine. The results were striking: the drug improved mucus flow so effectively that the asthmatic mice cleared mucus as well as mice that had never been exposed to the allergen. Higher doses produced even better results. The challenge, Evans cautions, is that the chemical bonds targeted by these drugs also appear in other proteins throughout the body. Finding a medication that breaks only mucin bonds without damaging other proteins remains a distant goal.

A second team, led by immunologist Helena Aegerter at Ghent University in Belgium, is taking a different angle. Aegerter and her colleagues have focused on Charcot-Leyden crystals—protein structures that form as byproducts when certain white blood cells called eosinophils die. These crystals accumulate in the mucus of asthma patients, making it thicker and harder to expel. More troubling, the crystals themselves trigger inflammation, which causes the body to produce even more mucus—a vicious cycle. Aegerter's team developed antibodies in llamas, then engineered them to attack the proteins that hold these crystals together. When tested on mucus samples from asthma patients, the antibodies successfully dissolved the crystals. In mice, the antibodies also neutralized the inflammatory response. The team is now working to develop a drug based on these findings. "Our strategy now is really to target the crystals at the heart of the mucus plug," Aegerter explained. "By getting rid of the crystals, hopefully that will end all the mucus production and inflammation that gets generated around these airways."

The third approach comes from Burton Dickey, a pulmonologist at MD Anderson Cancer Center in Texas, who has spent two decades studying mucin secretion. In 2022, Dickey's team identified a protein called synaptotagmin 2 (Syt2) that appears to be essential for the excessive mucus production seen in asthma. When researchers removed the Syt2 gene from mice and then exposed them to an inflammatory molecule called interleukin-13, the mice produced normal amounts of mucus instead of the excessive amounts typical of asthma. This suggested that Syt2 is specifically involved in overproduction, not in the baseline mucus that lungs need to function. Dickey's team then designed a molecule called PEN-SP9-Cy3 that blocks Syt2 activity. In tests with mice and human cells, the molecule significantly reduced mucin secretion. "We hope that someday when someone with a severe asthma attack goes to the emergency room, they can inhale our drug and it will prevent the mucus from continuing to plug up their airways," Dickey said.

For patients like Blessing Azeke, who has already spent months cycling between classrooms and emergency clinics, these developments offer a glimmer of possibility. If any of these three approaches proves effective in human trials, it could mean fewer midnight rushes to the hospital, fewer missed classes, fewer moments of gasping for breath. The work is still in early stages, but the direction is clear: researchers are no longer trying to patch one symptom at a time. They are learning to address the root mechanisms that turn mucus from a protective fluid into a life-threatening obstruction.