New Research Offers Hope for Untreatable Cystic Fibrosis

Scientists Identify Key to Drug Response in Genetic Variants

A breakthrough study is offering renewed optimism for the roughly 10% of individuals with cystic fibrosis who don’t respond to currently available medications. Researchers have pinpointed the molecular factors determining drug effectiveness, paving the way for personalized treatments.

Unlocking the Mystery of CFTR Variants

Cystic fibrosis, a genetic disease affecting mucus and other secretions, primarily impacts the lungs, causing breathing difficulties. While recent drug advancements have dramatically improved life expectancy for many, approximately 3 percent of patients harbor CFTR variants that remain unresponsive to these therapies. Eli Fritz McDonald, the study’s lead author, was driven to investigate this disparity.

“My cousin, Analiese, suffered from cystic fibrosis and passed away at the young age of 20 during my graduate studies,”

—Eli Fritz McDonald, Postdoctoral Fellow

The research, conducted by teams led by Lars Plate and Jens Meiler at Vanderbilt University, focused on understanding why some CFTR variants resist correction. The team discovered that even variants with mutations in similar regions exhibit varying degrees of protein instability.

Computational Biology Reveals Potential Solutions

Using a combination of computational structural biology and experimental chemical biology, the researchers found that introducing new mutations could compensate for the instability in poorly responsive variants. Remarkably, many of these modified variants then became susceptible to existing FDA-approved corrector drugs. According to the Cystic Fibrosis Foundation, over 30,000 people in the United States are living with cystic fibrosis (Cystic Fibrosis Foundation, 2024).

McDonald, who received the 2024 Dr. Anne Karpay Award in Structural Biology, leveraged the expertise of both the Plate and Meiler labs during his doctoral work. He explained that his unique co-advisement allowed him to integrate multiple levels of complexity into the research.

Precision Medicine on the Horizon

The findings suggest that developing new corrector drugs specifically tailored to these poorly responsive CFTR variants is a viable path forward. Plate envisions a future where patients with cystic fibrosis receive drug combinations optimized for their individual genetic profiles.

“In a perfect world, every patient would have drugs that they respond to,”

—Lars Plate, Chancellor Faculty Fellow

This research was supported by funding from the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences. The team hopes their work will bring effective treatments to those currently resistant to existing therapies.

McDonald is now continuing his research at St. Jude Children’s Hospital, focusing on the molecular basis of pediatric diseases.

Reference: McDonald EF, Kim M, Olson JA, Meiler J, Plate L. Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability. PNAS. 2025;122(17):e2418407122. doi: 10.1073/pnas.2418407122

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.