About this Research Topic
Cystic Fibrosis (CF) is a condition caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes for an ion channel mediating chloride and bicarbonate transport across epithelial cells. CF is a syndrome characterized by high sweat chloride concentration, pancreatic insufficiency, poor nutritional status, gastrointestinal symptoms, pulmonary exacerbations, and progressive loss of lung function until respiratory failure occurs. Following the clinical success of the first CFTR modulators, Ivacaftor (VX-770), Lumacaftor(VX-809), and Tezacaftor (VX-661), a number of research groups have shown that combinations of modulator molecules with complementary mechanisms of action are better in rescuing the misprocessing defect of F508del-CFTR than the single treatment of lumacaftor or Tezacaftor. Following the clinical success of the first CFTR modulators, the FDA and EMA recently approved the next-generation CFTR modulator Trikafta™.
Phase 3 clinical trials with Trikafta™ (VX-661+VX-445+VX-770) have shown dramatic improvement in lung function, reduction in pulmonary exacerbations, and improvement in the quality of life of patients carrying at least one F508del allele. However, the overall clinical effect size is variable among patients with the same genotype. Therefore, there is a need to understand the reason for this patient-to-patient variability. Moreover, the effects of Trikafta™ are unknown on the rare CFTR mutations. Currently, academic and industry laboratories are developing therapeutical strategies using patient-derived tissues. Therefore, in vitro screening of patient-specific responses to established or novel CFTR modulators could prove to be valuable to personalize combination therapy approaches. These efforts, however, are hampered by incomplete insights into the molecular mechanism of CFTR modulators and their efficacy to revert all pathophysiologic manifestations of cystic fibrosis.
This Research Topic welcomes Original Research, Review, and other article types focusing on, but not limited to, the following subjects:
• The mechanism of action for FDA approved and novel CFTR modulators
• Modifier genes that explain patient to patient clinical effect size variability
• Modifier genes as an alternative therapeutic approach
• Structural studies and molecular dynamic studies of modulator binding and their pro-folding action
• CFTR modulators effect on the biology of defects in CF (cytokines, lipids, ROS).
Phase 3 clinical trials with Trikafta™ (VX-661+VX-445+VX-770) have shown dramatic improvement in lung function, reduction in pulmonary exacerbations, and improvement in the quality of life of patients carrying at least one F508del allele. However, the overall clinical effect size is variable among patients with the same genotype. Therefore, there is a need to understand the reason for this patient-to-patient variability. Moreover, the effects of Trikafta™ are unknown on the rare CFTR mutations. Currently, academic and industry laboratories are developing therapeutical strategies using patient-derived tissues. Therefore, in vitro screening of patient-specific responses to established or novel CFTR modulators could prove to be valuable to personalize combination therapy approaches. These efforts, however, are hampered by incomplete insights into the molecular mechanism of CFTR modulators and their efficacy to revert all pathophysiologic manifestations of cystic fibrosis.
This Research Topic welcomes Original Research, Review, and other article types focusing on, but not limited to, the following subjects:
• The mechanism of action for FDA approved and novel CFTR modulators
• Modifier genes that explain patient to patient clinical effect size variability
• Modifier genes as an alternative therapeutic approach
• Structural studies and molecular dynamic studies of modulator binding and their pro-folding action
• CFTR modulators effect on the biology of defects in CF (cytokines, lipids, ROS).
Keywords: CFTR, correctors, potentiators, modifier genes, oxidative stress, inflammation
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