Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies

Gentzsch, Martina; Cholon, Deborah M.; Quinney, Nancy L.; Martino, Mary E. B.; Minges, John T.; Boyles, Susan E.; Lee, Tara N. Guhr; Esther, Charles R.; Ribeiro, Carla M. P.

doi:10.3389/fphar.2021.628722

Cited by 23 publications

(28 citation statements)

References 48 publications

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“…These responses were independent of increases in CFTR mRNA [58]. 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 [32], similar to the potentiating effect of SMM on CFTR rescue [58].…”

Section: Evaluation Of Cftr Rescue In Inflamed Airway Epithelia In Vitrosupporting

confidence: 57%

“…resulting from treatment with the CFTR corrector VX-661 and the potentiator VX-770 [32], similar to the potentiating effect of SMM on CFTR rescue [58]. [32].…”

Section: Evaluation Of Cftr Rescue In Inflamed Airway Epithelia In Vitromentioning

confidence: 73%

“…As SMM is obtained from CF lungs with severe disease, an additional model was developed where bronchoalveolar fluid (BALF) from pediatric CF patients with less severe disease was used in lieu of SMM [32]. Similar to the approach with SMM, BALF from CF patients contains the infectious and inflammatory factors to which the airway epithelia from pediatric patients are exposed.…”

Section: In Vitro Translational Models Of Cf Airway Epithelial Inflammationmentioning

confidence: 99%

“…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 [32,58] or BALF from pediatric CF patients [32]. 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).…”

Section: Evaluation Of Cftr Rescue In Inflamed Airway Epithelia In Vitromentioning

confidence: 99%

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Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Ribeiro

Gentzsch

2021

Cells

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Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit cystic fibrosis patients.

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Section: Evaluation Of Cftr Rescue In Inflamed Airway Epithelia In Vitrosupporting

confidence: 57%

“…resulting from treatment with the CFTR corrector VX-661 and the potentiator VX-770 [32], similar to the potentiating effect of SMM on CFTR rescue [58]. [32].…”

Section: Evaluation Of Cftr Rescue In Inflamed Airway Epithelia In Vitromentioning

confidence: 73%

Section: In Vitro Translational Models Of Cf Airway Epithelial Inflammationmentioning

confidence: 99%

Section: Evaluation Of Cftr Rescue In Inflamed Airway Epithelia In Vitromentioning

confidence: 99%

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Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Ribeiro

Gentzsch

2021

Cells

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“…The impact of the CF airway environment on these mechanisms remains unclear. Interestingly, a recent study showed beneficial effects of inflammation on CFTR rescue by modulator therapy in vitro [ 9 ].…”

Section: Pharmacodynamics Of Cftr Modulatorsmentioning

confidence: 99%

CFTR Modulators: Does One Dose Fit All?

Meer

Wilms

Heijerman

2021

JPM

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For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.

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Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis

Beswick,

Liu,

Overdevest

et al. 2024

The Laryngoscope

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ObjectivesThe 22‐question SinoNasal Outcome Test (SNOT‐22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT‐22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT‐22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF).MethodsProspective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT‐22 scores were obtained at baseline and after 3–6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution‐based methods were used to assess internal consistency and calculate the MCID of the SNOT‐22.ResultsA total of 184 PwCF participated with mean baseline SNOT‐22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre‐ and post‐HEMT data reported improvement in SNOT‐22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT‐22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02–1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14–18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39–20.11) were associated with greater SNOT‐22 improvement. The mean MCID calculated via distribution‐based methods was 8.5.ConclusionWorse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT‐22 in PwCF is 8.5 points, similar to non‐CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT‐22 has strong internal consistency in PwCF.Level of Evidence3 Laryngoscope, 2024

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Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies

Cited by 23 publications

References 48 publications

Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Impact of Airway Inflammation on the Efficacy of CFTR Modulators

CFTR Modulators: Does One Dose Fit All?

Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis

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