Blocking sodium channels helps patients breathe easier

Cystic Fibrosis (CF) is the most common lethal autosomal recessive hereditary disease in Caucasians estimated to affect approximately 55,000 individuals worldwide. The disease compromises many organs in the body, particularly the lungs and digestive system, which become clogged with sticky mucus. Patients with CF have difficulty breathing and digesting food and, in addition, are highly susceptible to fatal lung infections. Epithelial sodium channels (ENaCs) play a key role in maintaining fluid balance and mucus levels in the lungs. Over-active sodium channels can result in impaired lung function due to build-up of thickened (dehydrated) mucus in the lungs. Ongoing research seeks to discover potent ENaC antagonists that reduce the channel’s activity in disease models which could reduce disease complications and slow the decline of lung function in patients.

 

Understanding the mechanisms of the disease

Although it is a disease affecting epithelial cells in multiple organs (for example, the gut, pancreas, and lungs) it is the lung disease which is responsible for >90% of deaths, with a median life expectancy of 37 years for afflicted patients. The disease results from mutations in the cystic fibrosis transmembrane regulator (CFTR) gene which encodes for a cAMP-activated Chloride- channel. Over 1500 mutations in the CFTR gene have been described but the most frequent and detrimental mutation, ΔF508CFTR, accounts for over 70% of CF cases. This mutation results in protein misfolding and increased degradation within the cell, resulting in very little ΔF508CFTR activity.

 

Translating into treatment for patients

There is now compelling evidence that CF lung disease results from a failure of the body’s natural defense mechanisms as a consequence of dehydration of the mucus in the airways. Currently available tr eatments for CF only address the symptoms and do not address the underlying cause of the disease. A major improvement in raising median life expectancy to 37 years has been achieved over the last two decades. This reflects in large part, early and more aggressive treatment of airway infections with better antibiotics and better clinical management of nutrition and pancreatic function. Understanding of the cellular and molecular mechanisms underlying the pathogenesis of CF has increased rapidly in recent times. Insights into the structure and function of CFTR, the role and regulation of ENaC, together with the development and growing validation of the airway surface liquid depletion hypothesis have given fresh impetus to drug discovery and development for CF.

Investigating whether the blocking of sodium channels can help patients breathe easier is just one of the many hypotheses currently being researched within the NIBR CF team.

Learn more about our research in Respiratory Disease

 

Back to top