Discovery of Protein May Lead to New Asthma Treatments

In a new study published by Nature Communications, the authors discovered a protein that can cause airway constriction, mucus production, chest tightness, and difficulty breathing when missing or depleted.

These findings may lead to new, effective treatments for the 334 million patients worldwide who have asthma. Previously, the researchers discovered the SPLUNC1 protein while conducting cystic fibrosis studies, but they wondered how it may impact asthma.

"We first measured SPLUNC1 levels in airway samples obtained from asthmatics and normal volunteers in the UNC Center for Environmental Medicine, Asthma, and Lung Biology," said researcher Steve Tilley, MD. "We were astonished to find that SPLUNC1 levels were markedly reduced in people who have asthma."

In the study, mouse models of asthma were given allergens, and the SPLUNC1 were depleted in the airways, which is characteristic of human asthma. However, when replenished, the protein was able to reverse airway hyperresponsiveness.

Based on these findings, the team of researchers determined that the protein was able to regulate the contraction of the smooth muscle in the airways by preventing calcium from entering the muscles, according to the study. This suggests that SPLUNC1 deficiencies could lead to airway hyperresponsiveness, which is characteristic of asthma.

"People have been studying SPLUNC1 and its role in the context of other diseases, such as cystic fibrosis and lung cancer, but we believe that we are the group to identify its role in asthma," said researcher Robert Tarran, PhD.

The protein is produced by the epithelial cells that line the airway, according to the study.

“We found that this protein, which is actually turned off by excessive inflammation, is needed to cause the muscle to relax,” Dr Tarran said. “It's essentially a muscle-relaxing factor that's missing from asthma patients. It's something that normally acts as a brake.”

The authors suggest that a nebulizer- or inhaler-based treatment may present a method to replenish the protein, and treat asthma.

"Instances of asthma are much higher in the western world," Dr Tarran said. "Some of the highest countries are Australia, the UK, and the [United] States. The cost of asthma to the healthcare system in the US is quite big. Most of the asthma therapies people use are inhalers, which have been around for decades. There have only been a few new asthma medications in the past 10 or 20 years, and they're still being evaluated. This protein could be a potentially new target to go after, and it could really benefit a lot of people."

The researchers previously determined the crystal structure of the protein, which helped advance the current study.

"Since we know the crystal structure of the protein, we're able to find the active site of the protein that regulates smooth muscle contraction," Dr Tarran said. "So we can make peptides or drugs to target that active site and see if that works. That's one approach."

In the future, the investigators hope to study the therapeutic use of this protein in patients, according to the study.

"We want to study this in patients to correlate SPLUNC1 levels with airway hyper-reactivity," Dr Tarran said. "And we also want to go deeper into the mechanism -- how does this protein do what we observed. So there are several future avenues of research: expanding clinical studies, designing drugs in mouse studies, and then studying the underlying biology of what happens in a person with asthma."

While Dr Tilley has long been investigating asthma, he said that this latest discovery was the most exciting he has been involved with, according to the study.

"If we can further establish that SPLUNC1 is the elusive epithelial-derived relaxing factor that is deficient in asthmatics, then we can begin working on ways to restore SPLUNC1 levels in patients as a novel therapy to treat asthma,"Dr Tilley concluded. "I am looking forward to working with Drs. Neil Alexis, Ilona Jaspers, and David Peden in our asthma center to design more translational studies in humans so that we can determine the clinical significance and therapeutic potential of SPLUNC1 in asthma."