Overview of cystic fibrosis
Cystic fibrosis (CF) is a genetic disorder with multisystem involvement. The treatment of CF is complex and requires visits to specialized care centers and use of high-cost medications. The disease is caused by the presence of pathogenic variants in both alleles of the CFTR gene, which encodes the CFTR protein. This protein is a chloride and bicarbonate channel present in the apical surface of epithelial cells of different organs and systems in the human body. Defects in the synthesis and/or function of this protein result in clinical manifestations of varying intensity, including exocrine pancreatic insufficiency and nutrient malabsorption, progressive chronic lung disease, and high risk of dehydration and metabolic disorders, with a significant reduction in life expectancy. Available treatments in our setting manage to control these manifestations, not acting directly on the primary cause of CF. The treatment options include pancreatic enzyme replacement therapy administered with every meal to improve nutrient absorption, use of dietary supplements to improve calorie intake, use of mucolytics for pulmonary secretions, use of oral antibiotics or inhalers, and routine chest physical therapy to control pulmonary manifestations.
In Brazil, CF is on the list of diseases that are mandatory in neonatal screening testing, assessed via measurement of immunoreactive trypsinogen. Approximately 250 cases are diagnosed annually. Around 5,000 patients are currently registered with the Brazilian Cystic Fibrosis Registry, a database updated by health professionals working at over 50 care centers throughout the country. The patient registry has secure access and includes demographic, diagnostic (including genetic), and treatment and outcome data regarding CF, with periodic disclosure on the website www.gbefc.org.br.
CFTR modulators
Changes in the CFTR gene can affect the expression of the CFTR protein in epithelial cells and impair its function to a greater or lesser extent. The clinical status of a patient depends, therefore, on the resulting amount and function of the protein. The discovery of new drugs that modulate the function of the CFTR protein has generated great enthusiasm for patients and health professionals involved in the treatment of CF.
Such therapies target the cause of the disease, not only the consequences. The new CFTR modulator drugs that are commonly available are potentiators (which increase protein function) and correctors (which interfere with protein processing and result in increased protein expression on the apical surface of cells). The most common variant worldwide, named F508del, results in a protein processing defect, and the protein is not expressed on the cell surface.
Even when the protein is expressed through the effect of processing correctors, there remains a defect in the function and stability of the protein on the cell surface. Therefore, patients with variants such as F508del need both classes of modulators to correct the problem; in turn, patients with variants such as G551D or S549R, which affect protein function alone, need only a potentiator of the CFTR function.
First version created on August 21, 2019.
Luiz Vicente Ribeiro Ferreira da Silva Filho
Alberto de Andrade Vergara
Norberto Ludwig Neto
Brazilian Cystic Fibrosis Study Group (GBEFC)