New Insights into Molecular Causes of Cystic Fibrosis Drug Resistance

Breathing can be extremely challenging for individuals with cystic fibrosis (CF), a hereditary disease affecting various bodily secretions, particularly mucus. Normally, lung mucus is thin and slippery, facilitating easy airflow, but in CF patients, it becomes thick and sticky, blocking airways and causing persistent breathing difficulties similar to severe seasonal allergies. Over recent years, revolutionary medications targeting the CFTR protein—the defective ion channel responsible for CF—have improved the lives of many patients. However, not all CFTR mutations respond effectively to these therapies.

A groundbreaking study conducted by researchers Lars Plate and Jens Meiler, published in the Proceedings of the National Academy of Sciences, analyzed both responsive and resistant CFTR variants to uncover the molecular basis of drug response. The research utilized advanced computational structural biology and experimental chemistry techniques, aiming to understand why some CF mutations evade current treatments.

The study reveals that different CFTR mutations, even within the same region, cause varying degrees of protein destabilization. By inducing new mutations that stabilized these proteins, the team was able to restore responsiveness to existing CF drugs in many cases. This suggests that developing new drugs aimed at these poorly responsive variants could expand effective treatment options.

One motivating factor for this research was the personal story of the first author, Eli Fritz McDonald, whose cousin Analiese lost her battle with CF at age 20. Her illness was caused by mutations that current drugs could not effectively treat, highlighting the urgent need for more personalized therapies.

CFTR mutations are categorized into three types, with some leading to misfolded proteins that cannot function properly. Current treatments include corrector drugs that help these proteins fold correctly. Nonetheless, about 3% of CF patients harbor mutations that are poorly responsive to these correctors, leaving them with limited options.

The study’s findings show that, even among poorly responsive variants, some can be 'corrected' by introducing specific mutations that enhance protein stability, making them amenable to existing drugs. This paves the way for developing targeted therapies tailored to individual genetic profiles, a step toward precision medicine in CF treatment.

Dr. Lars Plate emphasizes that the goal is to provide every patient with drugs suited to their unique mutation profile, thereby maximizing treatment efficacy. This research offers hope that future therapies will be able to help those currently resistant to standard treatments.

Funding from the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences supported this work. The research exemplifies the collaboration among experts in protein folding, structural biology, and clinical medicine at Vanderbilt University, aiming to transform CF care through molecular insights and personalized approaches.