Cystic fibrosis (CF) is recessive autosomal disease triggered with the mutations in cystic fibrosis transmembrane regulator (CFTR) gene [1]. The CFTR gene encodes a cAMP-regulated chloride channel found in epithelial cells mainly in apical membrane. This channel facilitates movement of small ions through membranes. When this mechanism is dysregulated, it disrupts fluid and salt homeostasis, leading to multi-organ dysfunctions and ultimately resulting in mortality due to respiratory failure. For over seventy years, therapies for cystic fibrosis (CF) focused solely on alleviating symptoms rather than targeting the root cause: the altered CFTR gene. The mutations responsible for CF are dispersed throughout the CFTR gene, affecting both intronic and exonic regions [2]. Small molecules such as potentiators and correctors are that target the vast majority of CF-causing mutations by enhancing the processes and trafficking of the mutated CFTR protein. However, 10% of disease inducing variants do not respond to any currently available small-molecule therapies. Unlike CFTR modulators, which work on specific mutations, genetic interventions have the potential to target alterations at the root of the disease. More importantly, they could offer a solution which is permanent to cystic fibrosis. [3]
CF can be caused by mutations in the CFTR [cystic fibrosis transmembrane conductance regulator] gene, which codes a chloride and bicarbonate channel expressed in epithelial cells of various organs affected in this disease [5]. Roughly over 2000 CFTR gene alterations that have so far been described consist of frameshift (15.6%), missense (39.6%), nonsense (8.3%) and splicing (11.4%) mutations; and large (2.6%), in-frame (2.0%) deletions or insertions, promoter mutations (0.7%) and presumed non-pathological variants (15.0%). However, further research is required to grasp whether many of these cause disease. [6]
Despite intensive symptomatic treatments, most patients eventually develop progressive lung disease characterized by airway mucus obstruction, bacterial infection, and inflammation, as these treatments do not address the underlying molecular cause of the disease. Treatment of these symptoms include mucolytic for dissolving thick mucus, antibiotics for treating or preventing infections, and anti-inflammatory agents to reduce chronic inflammation. However, treatments that act upon the CFTR molecular defect are required to stop the chain of events that leads to lung disease progressively. Patients exhibit a wide range of clinical phenotypes, partly due to the approximately 2,000 CFTR gene mutations identified so far, of which only around 200 have been characterized in terms of their impact on the disease. [8] Other genetic, cellular, and environmental factors, which remain largely unknown, also modify the clinical course of the problem and also each individual’s response to therapy. [9].
Cystic fibrosis trigger a series of events that ultimately lead to severe lung deficiency. Most common therapies treat the symptoms (eg, mucolytic to dissolve the mucus which is thick). However, treatments that target molecular defects earlier in the disease progression, such as CFTR modulators, can prevent the development of end-stage lung disease. ENaC = epithelial sodium channel [6]