ArticleInternational journal of molecular sciences2023
Theratyping of the Rare CFTR Genotype A559T in Rectal Organoids and Nasal Cells Reveals a Relevant Response to Elexacaftor (VX-445) and Tezacaftor (VX-661) Combination.
Article in International journal of molecular sciences, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Novel insight into CFTR gene's single nucleotide variants classification via in-silico analysis of a conserved site.Journal of computer-aided molecular design · 2025Article
- Organoid-on-a-chip (OrgOC): Advancing cystic fibrosis research.Materials today. Bio · 2025Review
- The response of rare CFTR mutations to specific modulator combinations.ERJ open research · 2025Article
- Blood platelet reduction after elexacaftor/tezacaftor/ivacaftor treatment in people with cystic fibrosis may depend on systemic inflammation reduction.Scientific reports · 2025Article
- Pulmonary Function Modulates Epigenetic Age in Subjects with Cystic Fibrosis.International journal of molecular sciences · 2025Article
- Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators.Molecular and cellular pediatrics · 2025Review
- Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- How Effectively Can Oxidative Stress and Inflammation Be Reversed When CFTR Function Is Pharmacologically Improved?Antioxidants (Basel, Switzerland) · 2025Review
- Proteostasis Landscapes of Cystic Fibrosis Variants Reveals Drug Response Vulnerability.bioRxiv : the preprint server for biology · 2025Article
- Non pathological sweat test, pancreatic insufficiency and Cystic Fibrosis: an unusual case in a child with F508del-duplication of exons 1-3 CFTR genotype.BMC pediatrics · 2024Article
- The ageing of people living with cystic fibrosis: what to expect now?European respiratory review : an official journal of the European Respiratory Society · 2024Review
- CFTR modulators response of S737F and T465N CFTR variants on patient-derived rectal organoids.Orphanet journal of rare diseases · 2024Article
- Liver biochemical indexes and cholesterol metabolism in cystic fibrosis patients with F508del/CFTR variant genotype after elexacaftor/tezacaftor/ivacaftor treatment.Scientific reports · 2024Article
- Article
- One year of treatment with elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis homozygous for the F508del mutation causes a significant increase in liver biochemical indexes.Frontiers in molecular biosciences · 2023Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Despite the promising results of new CFTR targeting drugs designed for the recovery of F508del- and class III variants activity, none of them have been approved for individuals with selected rare mutations, because uncharacterized CFTR variants lack information associated with the ability of these compounds in recovering their molecular defects. Here we used both rectal organoids (colonoids) and primary nasal brushed cells (hNEC) derived from a CF patient homozygous for A559T (c.1675G>A) variant to evaluate the responsiveness of this pathogenic variant to available CFTR targeted drugs that include VX-770, VX-809, VX-661 and VX-661 combined with VX-445. A559T is a rare mutation, found in African-Americans people with CF (PwCF) with only 85 patients registered in the CFTR2 database. At present, there is no treatment approved by FDA (U.S. Food and Drug Administration) for this genotype. Short-circuit current (Isc) measurements indicate that A559T-CFTR presents a minimal function. The acute addition of VX-770 following CFTR activation by forskolin had no significant increment of baseline level of anion transport in both colonoids and nasal cells. However, the combined treatment, VX-661-VX-445, significantly increases the chloride secretion in A559T-colonoids monolayers and hNEC, reaching approximately 10% of WT-CFTR function. These results were confirmed by forskolin-induced swelling assay and by western blotting in rectal organoids. Overall, our data show a relevant response to VX-661-VX-445 in rectal organoids and hNEC with CFTR genotype A559T/A559T. This could provide a strong rationale for treating patients carrying this variant with VX-661-VX-445-VX-770 combination.
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Registered trials
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