In this blog post, we’ll explore the mechanisms behind the development of cystic fibrosis, its effects on the airways and pancreas, and how treatment for the disease has evolved—from past therapies to current CFTR modulators and research into gene-based therapies.
When people see a mother holding her child upside down and patting their chest, many might think, “The child and mother are having fun together. That’s such a heartwarming sight these days!” However, if told that the child is doing this out of necessity due to a life-threatening genetic disorder, most people would be shocked, and some might even find it hard to believe. In fact, children with cystic fibrosis may require respiratory physical therapy and airway clearance to remove the thick mucus that accumulates in their airways. In the past, this treatment was one of the most important aspects of daily care.
The surface of the airways, through which air enters the lungs, contains secretory cells that secrete sticky mucus, epithelial cells involved in the movement of chloride ions and water, and ciliated cells that remove mucus through ciliary movement. If the mucus secreted by the secretory cells does not receive adequate hydration, its viscosity increases, making it difficult to remove smoothly through ciliary movement alone and causing it to accumulate on the airway surface. Under normal conditions, the movement of chloride ions, sodium ions, and water by epithelial cells regulates the fluid balance on the airway surface, helping the mucus maintain an appropriate viscosity. However, in cystic fibrosis, mutations in the CFTR gene impair the function of the CFTR protein or prevent its sufficient production, leading to abnormalities in the movement of chloride ions and water. As a result, the mucus on the airway surface becomes excessively thick, making it difficult to clear and creating an environment conducive to bacterial growth. Cystic fibrosis is an autosomal recessive disorder; it is relatively common among European and North American Caucasian populations but is known to be very rare among Asian populations. However, the view that most cystic fibrosis patients die before the age of 35—as was the case in the past—no longer aligns with the current medical landscape. Significant advances in treatment have greatly extended life expectancy, and according to the Cystic Fibrosis Foundation’s 2025 patient registry data, half of cystic fibrosis patients born between 2021 and 2025 are projected to live to age 66 or older. However, this is a statistical projection for the population as a whole, and there can be significant variation depending on an individual’s genetic mutations, disease severity, and response to treatment.
To understand the pathogenesis of cystic fibrosis, let’s first examine how epithelial cells in a healthy person maintain fluid balance on the surface of the airways. The cell membrane of airway epithelial cells contains a protein called CFTR. CFTR stands for “cystic fibrosis transmembrane conductance regulator” and is a key channel protein that regulates the movement of chloride ions. Under normal conditions, various signaling pathways regulate CFTR activity; when chloride ions move out of the cell through CFTR, the movement of sodium ions and water is also regulated to maintain electrical and osmotic balance. In the signaling pathway involving guanine and its receptor, guanylate cyclase-C (GC-C), intracellular cGMP levels increase, thereby contributing to the regulation of ion transport. Meanwhile, regulation via cAMP and protein kinase A (PKA) also plays a significant role in CFTR activity. Therefore, rather than understanding this as a single, simple sequence in which cGMP is directly converted to cAMP, as previously described, it is more accurate to understand that multiple cellular signaling pathways regulate CFTR function.
Activated CFTR functions as a channel that transports chloride ions from inside the epithelial cells out of the cell. As chloride ion movement increases, the activity of other ion channels and transporters is also regulated, thereby maintaining the balance of salt and water across the cell membrane. Consequently, an appropriate amount of moisture is supplied to the airway surface, and this moisture plays a crucial role in keeping the mucus produced by secretory cells from becoming excessively viscous. Thus, in normal epithelial cells, CFTR and various other ion transporters interact to regulate the movement of chloride ions, sodium ions, and water, creating an environment in which mucus on the airway surface can be efficiently cleared by ciliary movement.
However, in patients with cystic fibrosis, mutations in the CFTR gene prevent the CFTR protein from functioning normally. Depending on the type of mutation, various functional abnormalities may occur; for example, the CFTR protein may not be produced at all, or even if it is produced, it may fail to properly reach the cell membrane, or it may be unable to allow sufficient chloride ions to pass through even after reaching the membrane. Consequently, in the epithelial cells of cystic fibrosis patients, the movement of chloride ions and water across the cell membrane does not occur properly. As a result, moisture on the surface of the airways decreases and mucus becomes excessively thick, making it difficult to clear. This thickened mucus accumulates in the bronchi and airways, causing recurrent infections and inflammation, which can gradually impair lung function.
The lungs and pancreas are the organs most significantly affected by cystic fibrosis in the human body. In a healthy person, when bacteria enter the airways, they adhere to the properly hydrated mucus covering the airway surface. This mucus is then transported toward the pharynx by the ciliary movement of ciliated cells and can be cleared from the airways through processes such as coughing or swallowing. Therefore, the mucus on the airway surface and ciliary movement serve as a crucial defense mechanism for clearing microorganisms that have entered from the outside. In contrast, in cystic fibrosis, dysfunction of the CFTR gene disrupts the water and salt balance on the airway surface, causing the mucus to become thick and sticky, which makes it difficult to clear effectively.
In healthy individuals, when bacteria enter the airways, even if they adhere to the mucus on the airway surface, the mucus viscosity is not excessively high, so the bacteria can be expelled from the airways through ciliary movement of ciliated cells and coughing. Therefore, even when bacteria enter the airways, the defense system composed of mucus and ciliary movement helps suppress infection. However, in patients with cystic fibrosis, when bacteria enter the airways, they may adhere to the highly viscous mucus and not be easily cleared. As a result, the bacteria remain in the airways and multiply, causing recurrent lung infections and potentially damaging the airways and lung tissue over the long term. In the lungs of people with cystic fibrosis, various pathogens—particularly ‘Pseudomonas aeruginosa’—can cause problems, and chronic infections can lead to bronchiectasis and reduced lung function.
Now you can understand why it is necessary for a mother to hold her child upside down and tap their chest. This action can be understood as a form of respiratory physical therapy that physically dislodges the thick mucus accumulated in the airways of cystic fibrosis patients to aid in its clearance. Today, mucus accumulated in the airways is removed not only by manual chest tapping but also through various airway clearance techniques and respiratory therapy devices. Airway clearance remains a crucial part of cystic fibrosis treatment and can be a particularly important therapeutic element for patients who cannot use CFTR modulators or who experience persistent lung infections and mucus problems. This is because failure to properly clear mucus from the airways facilitates bacterial growth, which can lead to recurrent infections and declining lung function.
Problems can also arise in the pancreas due to CFTR dysfunction. The pancreas produces secretions containing digestive enzymes, as well as water and bicarbonate, which enable the enzymes to travel to the intestines and function properly. In cystic fibrosis, abnormalities in the secretory function of the pancreatic ducts can cause highly viscous secretions to block the pancreatic ducts, leading to exocrine pancreatic insufficiency—a condition in which pancreatic enzymes are not adequately delivered to the intestines. As a result, fats, proteins, and carbohydrates in food may not be properly digested, and problems with nutrient absorption may arise.
The digestion of the food we consume involves a series of breakdown processes that ultimately transform it into nutrients in a form that can be absorbed. Digestive enzymes secreted by the pancreas play a crucial role in this digestive process. Therefore, if pancreatic exocrine function is impaired and digestive enzymes are not adequately delivered to the intestines, food cannot be fully digested, and it becomes difficult to properly absorb nutrients. In particular, problems with the digestion and absorption of fats can lead to steatorrhea, which may result in stunted growth and difficulty gaining weight in growing patients. For this reason, nutritional management—including pancreatic enzyme replacement therapy—is a crucial part of treatment for patients with cystic fibrosis. Therefore, rather than simply stating, as was often done in the past, that “no matter how much they eat, they don’t gain weight,” it is more accurate to understand that impairments in digestion and nutrient absorption can lead to difficulties with weight gain and growth.
Treatment methods for cystic fibrosis have advanced significantly, to a degree that is incomparable to the past. Currently, one of the most important treatments is therapy with CFTR modulators, which target dysfunction in the CFTR protein itself. CFTR modulators include potentiators, which enhance the function of the CFTR protein once it reaches the cell membrane so that it allows chloride ions to pass through more effectively, and correctors, which help misfolded CFTR proteins adopt a more normal conformation and move to the cell membrane. Currently in the United States, five CFTR modulators are approved: ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor, vanzacaftor/tezacaftor/deutivacaftor are approved in the United States; the leading triple combination therapies, Trikafta and Alyftrek, are used in patients of specific ages with certain CFTR mutations. In 2026, the FDA expanded the indications for Trikafta and Alyftrek, respectively, allowing more patients with mutations that produce the CFTR protein to be included in the treatment population. However, CFTR modulators are not equally effective for all CFTR mutations and should be used only after confirming the individual’s genetic mutation, age, and eligibility for treatment.
In addition to CFTR modulators, treatments to manage the symptoms and complications of cystic fibrosis are also important. Depending on the patient’s condition, treatments such as airway clearance techniques to remove mucus accumulated in the airways, inhalation therapies to thin mucus or support airway function, and antibiotic therapy to control bacterial infections are used. Patients with impaired exocrine pancreatic function undergo pancreatic enzyme replacement therapy, which involves taking pancreatic enzymes with meals and snacks, and receive vitamin and nutrient supplements as needed. Therefore, current cystic fibrosis treatment does not rely on a single, specific method to resolve the disease but rather involves a comprehensive approach tailored to the patient’s condition, combining therapies that improve the function of the CFTR gene itself with management of lung infections, mucus, and nutrition.
In the past, gene therapy using viral vectors such as adenoviruses or retroviruses to deliver a normal CFTR gene into the patient’s cells garnered significant attention. While adenovirus vectors can deliver genetic material into cells, they generally have limitations in ensuring long-term, stable gene expression; in contrast, retrovirus vectors were studied for their potential for long-term expression due to their ability to integrate genetic material into the cell’s genome. However, safety concerns—such as the possibility of insertion at unexpected locations during the integration process—have prevented these approaches from becoming the standard of care for cystic fibrosis. Therefore, as explained in a previous article, it is inaccurate to view adenovirus and retrovirus gene therapy as the most commonly used treatments for cystic fibrosis at present. Currently, gene therapy and RNA therapy continue to be developed as research areas aimed at providing the possibility of a curative treatment for a wider range of patients, including those who are difficult to treat with existing CFTR modulators.
Currently, there is no established cure for cystic fibrosis that can completely eliminate the disease in all patients with a single treatment. In particular, developing treatments for patients with mutations that prevent the production of the CFTR protein itself or for those in whom current CFTR modulators are not sufficiently effective remains a critical challenge. However, the treatment landscape for cystic fibrosis has changed significantly from the past. Whereas treatment in the past focused primarily on controlling infections, alleviating symptoms, and slowing disease progression, therapies that directly target the dysfunction of the CFTR protein—the root cause of the disease—are now in clinical use. Advances in CFTR modulators have played a key role in improving lung function and quality of life and significantly extending survival, and the latest registry data from the Cystic Fibrosis Foundation in the United States confirms that the survival outlook for cystic fibrosis patients continues to improve.
However, not all patients derive the same benefit from current treatments. Some patients may not be eligible for currently available CFTR modulators or may not receive adequate treatment due to reasons such as drug side effects. To overcome these limitations, researchers are exploring various approaches, including gene therapy—which delivers the function of the normal CFTR gene to cells—as well as mRNA therapy, which temporarily delivers the correct genetic information to enable the production of normal CFTR protein. mRNA therapy is a method of delivering genetic information to cells that enables the production of normal CFTR protein without altering the patient’s DNA itself; it is still at a stage requiring ongoing research. Although gene therapy and RNA therapy have not yet become established as standard treatments, they are regarded as important areas of research because they offer new treatment possibilities for patients in whom existing CFTR modulators are not sufficiently effective.
Therefore, cystic fibrosis is a disease for which the current treatment landscape has changed significantly, making it impossible to describe it simply as an “incurable, fatal genetic disease,” as was once believed. While the basic principle—that abnormalities in the CFTR gene cause problems in various organs, such as the airways and pancreas—remains unchanged, patients who receive an early diagnosis, ongoing specialized care, and appropriate CFTR modulators can now expect to live much longer lives than in the past. At the same time, research continues into new CFTR modulators, gene therapy, and RNA therapy for patients who have not yet fully benefited from current treatments. Although cystic fibrosis remains a disease for which no cure has been established, the fact that treatments targeting the underlying cause of the disease—going beyond past therapeutic limitations—have been introduced into clinical practice means we can place even greater hope in future research and therapeutic advancements.
