International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 20-32 http://medscipublisher.com/index.php/ijmms 25 5 Current Therapeutic Approaches in Cystic Fibrosis 5.1 CFTR modulators CFTR modulators are a cornerstone in the treatment of Cystic Fibrosis (CF), targeting the underlying genetic defect in the CFTR protein. These modulators are classified into three main categories: potentiators, correctors, and amplifiers. Potentiators, such as ivacaftor, enhance the function of CFTR proteins that reach the cell surface by increasing the channel's opening probability (Lopes-Pacheco, 2020). Correctors, including lumacaftor, tezacaftor, and elexacaftor, assist in the proper folding and trafficking of the CFTR protein to the cell membrane (Hanrahan et al., 2019; Southern et al., 2020; Heneghan et al., 2023). Amplifiers, a newer class, increase the amount of CFTR protein produced by the cell, thereby enhancing the efficacy of other modulators (Figure 3) (Lopes-Pacheco, 2020). Figure 3 From gene to protein structure (Adopted from Lopes-Pacheco, 2020a) Image caption: (A) CF transmembrane conductance regulator (CFTR) gene is located on the long arm of chromosome (Chr) 7. (B) The gene contains 27 exons and spans approximately 190 kb of human genomic DNA. (C) The mRNA is 6.2 kb long including the untranslated regions (Adapted from Collins, 1992). (D) The protein forms a chloride/bicarbonate channel composed of five domains: two transmembrane domains (TMD1 and TMD2), two nucleotide-binding domains (NBD1 and NBD2) and a regulatory domain (RD) (Adapted from Lopes-Pacheco, 2016). (E) The overall structure of human CFTR in the dephosphorylated, ATP-free conformation (Adapted from Liu et al., 2017 with permission from Prof. J. Chen). (F) The 2 075 CFTRgene variants that have so far been reported consist of missense (38.9%), frameshift (16.1%), splicing (11.1%), and nonsense (8.4%) mutations; in-frame (2.1%) and large (2.8%) deletions or insertions; promoter mutations (0.9%); and possibly non-pathogenic variants (13.0%) (Adapted from CFTR1 Database) (Adopted from Lopes-Pacheco, 2020a) The efficacy of CFTR modulators has been demonstrated in numerous clinical trials. For instance, the combination of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) has shown significant improvements in lung function, quality of life, and nutritional status in patients with at least one F508del mutation (Southern et al., 2020; Bacalhau et al., 2023; Heneghan et al., 2023). However, these therapies are not without limitations. Some patients experience adverse effects such as transient breathlessness and increased blood pressure with lumacaftor-ivacaftor (Southern et al., 2020; Heneghan et al., 2023). Additionally, the high cost and limited accessibility of these drugs pose significant challenges (Lopes-Pacheco, 2020). 5.2 Nutritional support Nutritional support is critical in managing CF due to the increased metabolic demands and malabsorption issues associated with the disease. High-calorie diets are recommended to meet the elevated energy requirements (Bailey et al., 2020). Pancreatic Enzyme Replacement Therapy (PERT) is essential for patients with pancreatic
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