Screening for Mucin Gene Mutation May Lead to Personalized IPF Prevention Therapy, Researcher Says

Genetic screening that can identify variants of the mucin-causing MUC5B gene — the key risk factor that predisposes people for idiopathic pulmonary fibrosis (IPF) — may hold the key to the development and administration of targeted therapies that may prevent the disease before it can progress and cause harm. 

The research behind this breakthrough — the identification of the role of that MUC5B gene — was led by David Schwartz, MD, professor of medicine and immunology, and chair of medicine at the University of Colorado (CU) Anschutz Medical Campus.

“We should be able to diagnose the disease before it destroys the lung, and we’ll be able to treat it and prevent the long-term complications of lung fibrosis and scarring,” Schwartz said in a press release written by Cathy Beuten.

IPF is a progressive lung disease of unknown cause that is characterized by increased scarring in lung tissues, resulting in shortness of breath and dry cough. To date, no cure has been found, and most treatments have focused on reversing or slowing down the tissue scarring. 

But that scarring oftentimes is already severe — and may have become irreversible — by the time IPF is diagnosed in many patients. The difficulty in diagnosing IPF is compounded by the fact that it’s often misidentified, given its clinical similarities to other chronic lung conditions, such as chronic obstructive pulmonary disease or frequent pneumonia.

Ideally, identifying the root causes of IPF before it scars the lungs would lead to preventative interventions, or treatments to halt progressive tissue damage.

In an effort to understand whether any genetic factors could contribute to the disease, Schwartz created an international IPF network of more than 60 researchers at more than 30 sites globally. The team collected and analyzed around 9,000 DNA samples from IPF patients who had close relatives who also had the disease. 

The analysis revealed that the most important IPF risk factor was a single change in the DNA sequence of the MUC5B gene. That variation resulted in the increased production of the main gel-forming protein in mucous, called mucin.

Mucous normally plays an important role in keeping the airways clear of dust particles and other potentially harmful agents. However, too much mucin can result in thicker mucous, and can interfere with the hair-like cilia that are in the airways to help in the process of mucous expulsion. Over the years, accumulation of mucous and airway contaminants can cause tissue scarring. 

The newly identified MUC5B variant was found to occur in one of each five people of European descent (non-Hispanic). It is much more frequent in people of European ancestry compared with people from African or Asian descent. Schwartz speculates that this MUC5B gene variant may have given children in ancient European populations an advantage against respiratory illnesses during adulthood.

This hypothesis was reinforced by the discovery that pulmonary fibrosis associated with rheumatoid arthritis — a disease that looks clinically similar to IPF — is associated with the same MUC5B variant risk factor. 

Based on these findings, the team believes that it is possible to develop personalized strategies to specifically treat people who carry the IPF-related MUC5B variant even before the disease onset.

Biological or therapeutic interventions can be applied, such inhaled medications, to reduced mucin production. That would prevent mucous build-up and subsequent lung tissue scarring. Such an approach may effectively block IPF in high-risk people before it begins. 

“I think that we’re going to move from a palliative approach to this disease to a preventive approach to this disease,” Schwartz said. “We can now tell clinicians, relatives of patients are at risk for developing pulmonary fibrosis. And we can use genetic tests to diagnose it earlier before it scars the lungs irreversibly. And, we’re in the process of developing treatments that are focused on MUC5B, on the cause of pulmonary fibrosis.”

“We’re trying to use what we have found for earlier diagnosis and gene-specific intervention,” he concluded.

To listen to a podcast on this topic featuring David Schwartz, click here.