Rectal organoid-guided CFTR modulator therapy restores lung function in a cystic fibrosis patient with the rare 1677delTA/R334W genotype

Mitropoulou, Georgia; Brandenberg, Nathalie; Hoehnel, Sylke; Ceroni, Camilla; Balmpouzis, Zisis; Blanchon, Sylvain; Dorta, Gian; Sauty, Alain; Koutsokera, Angela

doi:10.1183/13993003.01341-2022

Cited by 7 publications

(6 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the R334W mutation causes neither folding nor trafficking impairment, some studies have demonstrated that R334W-CFTR-dependent chloride secretion can be enhanced by increasing the number of R334W-CFTR channels at the plasma membrane with correctors, such as VX-809 and VX-661 [ 39 , 40 , 46 , 61 ]. In a recent report, intestinal organoids from an individual with CF (1677delTA/R334W) were incubated with VX-770, VX-809/VX-770, VX-661/VX-770 and VX-445/VX-661/VX-770 [ 62 ]. Upon Fsk stimulation, an increase in FIS values was observed with the different modulator combinations but to a comparable extent to that of VX-770 alone [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…In a recent report, intestinal organoids from an individual with CF (1677delTA/R334W) were incubated with VX-770, VX-809/VX-770, VX-661/VX-770 and VX-445/VX-661/VX-770 [ 62 ]. Upon Fsk stimulation, an increase in FIS values was observed with the different modulator combinations but to a comparable extent to that of VX-770 alone [ 62 ]. Another report assessed the efficacy of VX-445/VX-661/VX-770 in F508del/R334W intestinal organoid-derived epithelial monolayers and demonstrated rescue of CFTR-mediated anion transport [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau

Ferreira

Silva

et al. 2023

JPM

View full text Add to dashboard Cite

The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose–response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau

Ferreira

Silva

et al. 2023

JPM

View full text Add to dashboard Cite

show abstract

“…Indeed, a high correlation between modulator-promoted responses in intestinal organoids and alterations in SCC and ppFEV1 in PwCF carrying common and rare variants has been reported in several studies [24,50,53]. Moreover, modulator-promoted responses in intestinal organoids have served as a basis for guiding eligibility for compassionate use and to obtain health insurance coverage for individuals carrying non-eligible responsive CFTR variants [54,58].…”

Section: Intestinal Organoidsmentioning

confidence: 96%

Laboratory Tools to Predict CFTR Modulator Therapy Effectiveness and to Monitor Disease Severity in Cystic Fibrosis

Bacalhau,

Camargo,

Lopes-Pacheco

2024

JPM

View full text Add to dashboard Cite

The implementation of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has been attaining remarkable therapeutic outcomes for CF, a life-threatening autosomal recessive genetic disease. However, there is elevated CFTR allelic heterogeneity, and various individuals carrying (ultra)rare CF genotypes remain without any approved modulator therapy. Novel translational model systems based on individuals’ own cells/tissue are now available and can be used to interrogate in vitro CFTR modulator responses and establish correlations of these assessments with clinical features, aiming to provide prediction of therapeutic effectiveness. Furthermore, because CF is a progressive disease, assessment of biomarkers in routine care is fundamental in monitoring treatment effectiveness and disease severity. In the first part of this review, we aimed to focus on the utility of individual-derived in vitro models (such as bronchial/nasal epithelial cells and airway/intestinal organoids) to identify potential responders and expand personalized CF care. Thereafter, we discussed the usage of CF inflammatory biomarkers derived from blood, bronchoalveolar lavage fluid, and sputum to routinely monitor treatment effectiveness and disease progression. Finally, we summarized the progress in investigating extracellular vesicles as a robust and reliable source of biomarkers and the identification of microRNAs related to CFTR regulation and CF inflammation as novel biomarkers, which may provide valuable information for disease prognosis.

show abstract

“…Mitropoulou and collaborators reported a case in which intestinal organoids from a 19-year-old woman (1677delA/R334W) were used to select which clinically approved modulator therapy could be suitable for this individual [ 63 ]. Organoids were treated with IVA, LUMA-IVA, TEZA-IVA, and ETI, and an increase in forskolin-induced swelling values was observed with the different modulator combinations but to a comparable extent to that of IVA monotherapy.…”

Section: Clinical Outcomes Of Eti Therapy In Case Reports Observation...mentioning

confidence: 99%

“…These findings suggest that modulator combinations would provide similar clinical benefits to that of IVA monotherapy to this individual. Accordingly, she started to receive IVA monotherapy and exhibited a significant improvement in ppFEV1 (from 61% to 99%) and SCC (−26 mmol/L) within 9 months of therapy [ 63 ].…”

Section: Clinical Outcomes Of Eti Therapy In Case Reports Observation...mentioning

confidence: 99%

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

et al. 2023

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a potentially fatal monogenic disease that causes a progressive multisystemic pathology. Over the last decade, the introduction of CF transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has profoundly modified the lives of many people with CF (PwCF) by targeting the fundamental cause of the disease. These drugs consist of the potentiator ivacaftor (VX-770) and the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). In particular, the triple combination of CFTR modulators composed of elexacaftor, tezacaftor, and ivacaftor (ETI) represents a life-changing therapy for the majority of PwCF worldwide. A growing number of clinical studies have demonstrated the safety and efficacy of ETI therapy in both short- and long-term (up to two years of follow-up to date) and its ability to significantly reduce pulmonary and gastrointestinal manifestations, sweat chloride concentration, exocrine pancreatic dysfunction, and infertility/subfertility, among other disease signs and symptoms. Nevertheless, ETI therapy-related adverse effects have also been reported, and close monitoring by a multidisciplinary healthcare team remains vital. This review aims to address and discuss the major therapeutic benefits and adverse effects reported by the clinical use of ETI therapy for PwCF.

show abstract

Rectal organoid-guided CFTR modulator therapy restores lung function in a cystic fibrosis patient with the rare 1677delTA/R334W genotype

Cited by 7 publications

References 29 publications

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Laboratory Tools to Predict CFTR Modulator Therapy Effectiveness and to Monitor Disease Severity in Cystic Fibrosis

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

Contact Info

Product

Resources

About