Journal: ERJ Open Research

Article Title: BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport

doi: 10.1183/23120541.00445-2024

Figure Lengend Snippet: Effect of long-term BOS-318 treatment in combination with ETI on ion channel function. Cystic fibrosis human bronchial epithelial cells were treated with either vehicle or BOS-318 in the presence or absence of elexacaftor–tezacaftor–ivacaftor (ETI) for 48 h. After the treatment period, baseline I eq was established, followed by the sequential addition of 10 µM amiloride, 20 µM forskolin, 20 µM CFTRinh-172 and 100 µM UTP. (a) Representative equivalent current (I eq ) recordings. (b) CFTRinh-172-sensitive I eq representing CFTR activity. (c) Amiloride-sensitive I eq , representing epithelial sodium channel (ENaC) activity. n≥5 individual inserts from three donors. Statistical analyses were performed using a Kruskal–Wallis test and Dunn's multiple comparisons test in comparison to the relevant dimethylsulfoxide control. *: p≤0.05; **: p≤0.01. CFTR: cystic fibrosis transmembrane conductance regulator.

Article Snippet: CFTR modulators (VX-661 and VX-770) were from Adooq Biosciences (Irvine, CA, USA).

Techniques: Activity Assay, Comparison, Control

Journal: ERJ Open Research

Article Title: BOS-318 treatment enhances elexacaftor–tezacaftor–ivacaftor-mediated improvements in airway hydration and mucociliary transport

doi: 10.1183/23120541.00445-2024

Figure Lengend Snippet: BOS-318 treatment enhances ETI-mediated improvements in MCT. Cystic fibrosis human bronchial epithelial cells were treated with vehicle, BOS-318, elexacaftor–tezacaftor–ivacaftor (ETI) or a combination of ETI and BOS-318, in the presence of 30 nM vasoactive intestinal peptide, for 48 h. The mucociliary transport (MCT) rate was determined by tracking fluorescently labelled microspheres on the apical surface of the cells. (a) MCT rate shown as μm·s −1 and (b) MCT rate shown as a % of triple CFTR modulator therapy rate. n=7 individual inserts from four cystic fibrosis donors. Statistical analyses were performed using a Mann–Whitney U-test. **: p≤0.01. CFTR: CF transmembrane conductance regulator; DMSO: dimethylsulfoxide.

Article Snippet: CFTR modulators (VX-661 and VX-770) were from Adooq Biosciences (Irvine, CA, USA).

Techniques: MANN-WHITNEY

Journal: Journal of Experimental Pharmacology

Article Title: Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

doi: 10.2147/JEP.S255377

Figure Lengend Snippet: Pharmacological Therapies Commonly Used in Therapeutic Regimens of Individuals with Cystic Fibrosis

Article Snippet: These molecules were demonstrated to rescue mutant CFTR carrying G551D, G178R, R334W, S549N or F508del – the latter in combination with either VX-809 or ABBV-2222 – in both cell lines and CF HBE., , Patch-clamp functional studies showed that ABBV-974 and GLPG-2451 reduce the closed time and increase the open time of CFTR channels by a similar mechanism to that of VX-770, as no additive effects were observed when these molecules were tested together., , ABBV-3067 is another potentiator developed by Abbvie that was demonstrated to rescue F508del-CFTR in combination with the corrector ABBV-2222, and this combination is currently under clinical investigation (NCT03969888).

Techniques: Binding Assay, Translocation Assay, Clinical Proteomics, Membrane, Permeability, Muscles, Activation Assay, Inhibition, Phospho-proteomics, Activity Assay, Expressing, Transmigration Assay, Recombinant, Saline

Journal: Journal of Experimental Pharmacology

Article Title: Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

doi: 10.2147/JEP.S255377

Figure Lengend Snippet: Modulation of ion channels/transporters as alternative therapies for CF. In healthy airways, CFTR, ENaC, TMEM16A and SLC26A9 are expressed at the plasma membrane (PM) of epithelial cells where they contribute to ion and water homeostasis. In CF airways, due to the absence of functional CFTR, Cl – secretion is compromised and Na + absorption is upregulated, leading to a dehydrated air surface liquid (ASL) and impaired mucociliary clearance (MCC). Expression of TMEM16A and SLC26A9 at the PM are also diminished in CF ciliated cells, although the role of TMEM16A overexpression in secretory cells and its role in mucus secretion are still controversial. Alternative therapies for CF thus include blocking ENaC, enhancing SLC26A9 expression at the PM, and modulating TMEM16A. Although for the latter is still not clear whether activators or inhibitors are beneficial, a TMEM16A potentiator in currently under clinical investigation.

Article Snippet: These molecules were demonstrated to rescue mutant CFTR carrying G551D, G178R, R334W, S549N or F508del – the latter in combination with either VX-809 or ABBV-2222 – in both cell lines and CF HBE., , Patch-clamp functional studies showed that ABBV-974 and GLPG-2451 reduce the closed time and increase the open time of CFTR channels by a similar mechanism to that of VX-770, as no additive effects were observed when these molecules were tested together., , ABBV-3067 is another potentiator developed by Abbvie that was demonstrated to rescue F508del-CFTR in combination with the corrector ABBV-2222, and this combination is currently under clinical investigation (NCT03969888).

Techniques: Clinical Proteomics, Membrane, Functional Assay, Expressing, Over Expression, Blocking Assay

Journal: Journal of Experimental Pharmacology

Article Title: Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

doi: 10.2147/JEP.S255377

Figure Lengend Snippet: TMEM16A Activators

Article Snippet: These molecules were demonstrated to rescue mutant CFTR carrying G551D, G178R, R334W, S549N or F508del – the latter in combination with either VX-809 or ABBV-2222 – in both cell lines and CF HBE., , Patch-clamp functional studies showed that ABBV-974 and GLPG-2451 reduce the closed time and increase the open time of CFTR channels by a similar mechanism to that of VX-770, as no additive effects were observed when these molecules were tested together., , ABBV-3067 is another potentiator developed by Abbvie that was demonstrated to rescue F508del-CFTR in combination with the corrector ABBV-2222, and this combination is currently under clinical investigation (NCT03969888).

Techniques: Activation Assay, Binding Assay