Cystic fibrosis (CF) is a genetic disorder that impacts multiple organ systems within the body. At its core, CF arises from defects in a specific protein known as the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Understanding the function and malfunction of this protein is fundamental to grasping the mechanisms of the disease and the rationale behind its treatments. The CFTR protein’s role in maintaining fluid balance across cell surfaces is compromised in individuals with CF, leading to widespread effects.
The CFTR Protein’s Essential Function
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein acts as a channel embedded within the membranes of cells found in various organs, including the lungs, pancreas, sweat glands, and digestive tract. This protein facilitates the movement of negatively charged chloride ions into and out of cells. This transport helps regulate water movement across tissues, necessary for producing thin, free-flowing mucus and other secretions.
In the lungs, the CFTR channel moves chloride ions from inside cells to the outside, drawing water with them. This water layer allows tiny hair-like structures called cilia to sweep mucus up and out of the airways. The CFTR protein also influences the function of other channels, such as those transporting positively charged sodium ions. This coordinated ion and water movement maintains the fluidity of mucus, which lubricates and protects various bodily systems.
What Goes Wrong in Cystic Fibrosis
Cystic fibrosis stems from mutations in the CFTR gene, which provides the instructions for making the CFTR protein. Over 2,000 different mutations have been identified in this gene, each affecting the protein. These genetic changes can lead to a CFTR protein that is not produced, is misfolded, or does not function correctly as a channel.
The most common mutation, F508del, involves the deletion of three nucleotides, resulting in the loss of a phenylalanine amino acid at position 508 of the protein. This mutation causes the CFTR protein to misfold and degrade before reaching the cell surface. Other mutations may result in a protein that reaches the cell surface but has reduced chloride ion transport, or one that is unstable and quickly removed. Regardless of the specific mutation, the core problem is the CFTR protein’s inability to effectively transport chloride ions and, consequently, water.
How Faulty CFTR Protein Impacts the Body
The impaired function or absence of the CFTR protein leads to an imbalance of salt and water transport across cell surfaces, resulting in thick, sticky mucus. In the lungs, this mucus clogs the airways, leading to chronic infections and inflammation. This persistent obstruction and infection can cause damage to the airways, progressively reducing lung function.
The pancreas is also affected, as thickened secretions block the ducts that carry digestive enzymes to the small intestine. This blockage prevents enzymes from reaching food, leading to malabsorption of nutrients, particularly fats, and can result in fatty stools and malnutrition. Trapped enzymes can damage the pancreas itself. Individuals with CF may also experience issues in sweat glands, where defective CFTR leads to reduced reabsorption of salt, causing excessively salty sweat.
Targeting the CFTR Protein with Treatments
Modern treatments for cystic fibrosis, known as CFTR modulators, directly address the underlying protein defect rather than just managing symptoms. These targeted therapies aim to improve the function, quantity, or localization of the faulty CFTR protein. Different types of CFTR modulators exist, each designed to correct specific protein problems.
Potentiators, such as ivacaftor, bind to the CFTR protein at the cell surface, holding its gate open to allow more chloride ions to flow. Correctors, like lumacaftor and tezacaftor, help misfolded CFTR protein achieve the correct shape, enabling it to move to the cell surface and remain longer. Some therapies combine correctors and potentiators to address both the trafficking and gating defects of the protein. Amplifiers, currently under investigation, aim to increase the overall amount of CFTR protein a cell produces. These advancements have significantly improved the quality of life and outcomes for many individuals with cystic fibrosis.