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Gentzsch, M. Inflammation Enhances the Efficacy of CFTR Modulator Therapy. Encyclopedia. Available online: (accessed on 22 June 2024).
Gentzsch M. Inflammation Enhances the Efficacy of CFTR Modulator Therapy. Encyclopedia. Available at: Accessed June 22, 2024.
Gentzsch, Martina. "Inflammation Enhances the Efficacy of CFTR Modulator Therapy" Encyclopedia, (accessed June 22, 2024).
Gentzsch, M. (2021, November 30). Inflammation Enhances the Efficacy of CFTR Modulator Therapy. In Encyclopedia.
Gentzsch, Martina. "Inflammation Enhances the Efficacy of CFTR Modulator Therapy." Encyclopedia. Web. 30 November, 2021.
Inflammation Enhances the Efficacy of CFTR Modulator Therapy

The cystic fibrosis lung is inflamed and therefore the impact of inflammation on CFTR rescue should be considered. There is now evidence that airway inflammation enhances CFTR rescue. The development of CFTR modulators, such as correctors that augment F508del CFTR transfer to the apical membrane, and potentiators that increase CFTR channel activity, permitted successful treatment of the basic defect in cystic fibrosis. The first FDA-approved CFTR modulator was the potentiator ivacaftor (VX-770), which improves the function of the gating mutant G551D CFTR. While the potentiator VX-770 or the CFTR corrector lumacaftor (VX-809) alone did not significantly improve lung function in F508del CF patients, combining VX-809 with VX-770 (in the drug Orkambi) or combining the newer corrector tezacaftor (VX-661) with VX-770 (in the drug Symdeko) resulted in modest lung function improvements in clinical trials in patients homozygous for F508del CFTR. Notably, F508del rescue resulting from these combination therapies or the clinically effective novel triple therapy (in the drug Trikafta) were enhanced by airway epithelial inflammation in vitro. Thus, the airway inflammatory milieu improves the efficacy of CFTR modulators.

CFTR airway inflammation

1. Evaluation of CFTR Rescue in Inflamed Airway Epithelia In Vitro

Previous studies have indicated that various cytokines, including IL-1β, IL-4, TNFα, IL-10, and IL-13, enhance CFTR activity [1][2][3][4][5]. In contrast, the inflammatory mediator TGFβ might have a negative impact on CF transmembrane conductance regulator (CFTR) expression and F508del CFTR rescue. For instance, TGFβ has been shown to decrease the levels and function of apical CFTR in airway cells from non-CF subjects [6][7]. In addition, TGFβ has been reported to decrease CFTR biogenesis and inhibit the rescue of F508del CFTR [8]. A previous study has also indicated that a short exposure time (6 h) to a single bacterial stimulus, Pseudomonas aeruginosa, causes a reduction in Cl secretion by rescued F508del [9]. These studies indicate that individual inflammatory mediators can enhance or inhibit CFTR expression and function and, thus, can have different impacts on CFTR rescue.
Until recently, no studies have been conducted to evaluate the efficacy of CFTR modulators in CF airway epithelia that have been inflamed by the native CF airway milieu containing various inflammatory mediators. To test the effect of CFTR modulators in in vitro translational models of inflammation relevant to CF airways, we utilized F508del/F508del primary cultures of CF HBE mucosally exposed to SMM [10][11] or BALF from pediatric CF patients [10]. Our first study indicated that SMM exposure potentiated F508del CFTR activity resulting from the treatment with the CFTR corrector VX-809 and the potentiator VX-770 (Figure 1A,B). SMM exposure also enhanced the formation of the mature (band C) F508del CFTR triggered by the treatment with the CFTR modulators (Figure 1C,D) [11]. These responses were independent of increases in CFTR mRNA [11]. In a subsequent study, we demonstrated that exposure of F508del CF HBE cultures to BALF from CF children enhanced CFTR activity (Figure 2A) and maturation (Figure 2B) resulting from treatment with the CFTR corrector VX-661 and the potentiator VX-770 [10], similar to the potentiating effect of SMM on CFTR rescue [11].
Figure 1. Exposure of CF HBE to SMM enhances F508del CFTR rescue. (AD): CF HBE (F508del/F508del) cultures were exposed for 24 h to vehicle or 5 µM VX-809 in combination with 30 µL mucosal PBS or SMM. (A) Representative short-circuit currents (Isc, µA/cm2) recorded in Ussing chambers. (B) Quantification of F508del-mediated responses to forskolin (Fsk, 10 µM) + VX-770 (1 µM) and CFTRinh-172 (10 µM). (C) Representative Western blot of immunoprecipitated CFTR and tubulin controls. (D) Quantification of band C as % values normalized from band C values from control (vehicle- and PBS-treated CF HBE). (E) SMM overcomes chronic VX-770 treatment (5 μM, 48 h)-mediated abrogation of VX-809-promoted F508del CFTR rescue. (F) SMM overcomes chronic VX-770 treatment (5 μM, 48 h)-mediated abrogation of VX-661-dependent F508del rescue. (G) SMM enhances triple combination-promoted F508del CFTR rescue. CFTR responses to acute forskolin + VX-770 from F508del/F508del HBE in Ussing chambers. HBE were treated with VX-659 (1 µM), VX-661 (5 µM), and VX-770 (5 µM). All data are expressed as mean ± SEM. (AF): n = 3–4 CF HBE donors, 3–4 cultures/donor. (G): 2 CF HBE donors, 5–6 cultures/donor. * p < 0.05. (AD): Modified from Gentzsch et al., 2018 [11] (reproduced with permission of the ©ERS 2021: European Respiratory Journal 52 (6) 1801133; doi: 10.1183/13993003.01133-2018 Published 20 December 2018). (EG): Modified from Gentzsch et al., 2021 [10].
Figure 2. Exposure of CF HBE to pediatric BALF enhances F508del CFTR rescue. (A) CFTR responses from F508del/F508del HBE cultures evaluated in Ussing chambers. Cultures were apically exposed to 30 µM BALF or SMM and serosally treated with vehicle or 5 µM VX-661. Data are expressed as mean ± SEM. ns = not significant; 2 donors, five to six cultures/experimental group. (B) Representative CFTR Western blot to analyze F508del maturation (upper band); (C) IL-8 secretion (pg/mL of culture media) from the F508del/F508del HBE evaluated in (A). * p < 0.05. Data are expressed as mean ± SEM. Modified from Gentzsch et al., 2021 [10].
Strikingly, inflammation can also overcome the destabilization effect of chronic VX-770 exposure on CFTR rescue. Previously, we have established that chronic treatment with VX-770 abrogates corrector-mediated rescue of F508del by enhancing internalization and turnover of mature CFTR proteins [12]. Subsequently, we demonstrated that SMM exposure enhanced F508del CFTR responses to chronic treatment with VX-809 (Figure 1E) or VX-661 (Figure 1F) plus VX-770 by overcoming chronic VX-770-promoted inhibition of F508del rescue [10]. We have also shown that chronic VX-770 treatment inhibits UTP-induced activation of the calcium-activated chloride channel (CaCC) [12]. However, in follow-up studies, we demonstrated that the inhibitory effect of VX-770 on UTP-induced CaCC responses was reversed by exposing the F508del cultures to SMM [10]. Thus, whilst chronic VX-770 treatment can decrease F508del CFTR and CaCC activities, the inhibitory effect of VX-770 is overcome by airway epithelial inflammation.
Notably, the enhancing effect of SMM on CFTR rescue is also observed in CF HBE cultures treated with various combinations of modulators, including a triple combination (Figure 1G).

2. Airway Inflammation Enhances CFTR Modulator Therapy-Improved Lung Function In Vivo

The above studies demonstrated that the CF airway inflammatory milieu has a positive impact on the rescuing activity of CFTR modulators. In addition, as discussed earlier, various publications have reported an enhancement in CFTR function by certain cytokines in vitro [1][2][3][4][5]. However, little is known regarding whether airway inflammation affects the rescue of mutant CFTR in CF subjects.
Recently, Rehman et al. reported that inflammation enhances the response to CFTR modulators in vitro and in vivo [13]. The in vitro studies employed TNFα and IL-17 as inflammatory stimuli [13], and their findings are in agreement with our previous in vitro studies demonstrating that the CF airway inflammatory milieu enhances the efficacy of CFTR modulators [10][11]. As the stability of band C was not evaluated and band B was not detected in the study by Rehman et al. [13], the mechanism for the enhanced F508del CFTR rescue by TNFα and IL-17 remains unclear.
Importantly, Rehman et al. observed a positive correlation between airway inflammation and lung function improvement in CF patients treated with VX-770 [13]. As the majority of the G551D and R117H patients in the study by Rehman et al. had F508del in one allele [13], we speculate that maturation of F508del may have been increased by inflammation, contributing, at least in part, to the observed clinical improvement. This is supported by the observation that inflammation enhances the ER folding capacity [14][15][16][17], which may facilitate rescue of misfolded CFTR [10]. Furthermore, because we have demonstrated that R117H is also a folding mutant [18], it may exhibit improved folding in the presence of inflammatory stimuli. As discussed above, although VX-770 destabilizes rescued F508del [12][19], inflammation can overcome the detrimental effects of chronic exposure to ivacaftor [10]. Hence, we speculate that through a mechanism involving inflammation-dependent CFTR stabilization, the efficacy of chronic VX-770 treatment is improved in CF patients, resulting in increases in forced expiratory volume in 1 s (FEV1), as observed by Rehman et al. [13].
Additional studies are needed to examine the mechanism(s) responsible for the augmentation of CFTR rescue under inflammatory conditions. Addressing how inflammation enhances the efficacy of CFTR modulators might lead to novel therapies exploiting the beneficial effects of inflammation on CFTR rescue, while mitigating its harmful consequences to CF airways.


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