ArticleCellular and molecular life sciences : CMLS2022
Targeting the E1 ubiquitin-activating enzyme (UBA1) improves elexacaftor/tezacaftor/ivacaftor efficacy towards F508del and rare misfolded CFTR mutants.
Article in Cellular and molecular life sciences : CMLS, 2022. 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, 20 citations in OpenAlex.
- RFFL antisense oligonucleotides: A novel stabilization strategy to broaden the reach of CFTR modulator therapy.Molecular therapy. Nucleic acids · 2026Article
- Reconstitution of CFTR ubiquitination identifies lysine-420 as a regulator of cell surface residence and current.Biochemistry and biophysics reports · 2026Article
- Antisense oligonucleotide targeting the E3 ligase RFFL potentiates CFTR modulator efficacy in CF primary bronchial epithelial cells.Molecular therapy. Nucleic acids · 2025Article
- Real-Life in Cystic Fibrosis Pediatric Patients Treated With Kaftrio: A Descriptive Observational Study.Clinical pediatrics · 2025Observational
- p.Phe508del-CFTR Trafficking: A Protein Quality Control Perspective Through UPR, UPS, and Autophagy.International journal of molecular sciences · 2025Review
- Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases.Israel journal of chemistry · 2024Article
- Investigation of CFTR Function in Human Nasal Epithelial Cells Informs Personalized Medicine.American journal of respiratory cell and molecular biology · 2024Article
- Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?Cellular and molecular life sciences : CMLS · 2024Review
- Advances in the study of protein folding and endoplasmic reticulum-associated degradation in mammal cells.Journal of Zhejiang University. Science. B · 2024Review
- SUMOylation Inhibition Enhances Protein Transcription under CMV Promoter: A Lesson from a Study with the F508del-CFTR Mutant.International journal of molecular sciences · 2024Article
- Small-molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states.Molecular biology of the cell · 2024Article
- Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor-Ivacaftor.Frontiers in pharmacology · 2023Review
- KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR.International journal of molecular sciences · 2022Article
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- S945L-CFTR molecular dynamics, functional characterization and tezacaftor/ivacaftor efficacyFrontiers in pediatrics · 2022Article
- Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients With Severe Lung Disease Carrying Previously Ineligible CFTR Mutations.Open respiratory archivesArticle
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The advent of Trikafta (Kaftrio in Europe) (a triple-combination therapy based on two correctors-elexacaftor/tezacaftor-and the potentiator ivacaftor) has represented a revolution for the treatment of patients with cystic fibrosis (CF) carrying the most common misfolding mutation, F508del-CFTR. This therapy has proved to be of great efficacy in people homozygous for F508del-CFTR and is also useful in individuals with a single F508del allele. Nevertheless, the efficacy of this therapy needs to be improved, especially in light of the extent of its use in patients with rare class II CFTR mutations. Using CFBE41o- cells expressing F508del-CFTR, we provide mechanistic evidence that targeting the E1 ubiquitin-activating enzyme (UBA1) by TAK-243, a small molecule in clinical trials for other diseases, boosts the rescue of F508del-CFTR induced by CFTR correctors. Moreover, TAK-243 significantly increases the F508del-CFTR short-circuit current induced by elexacaftor/tezacaftor/ivacaftor in differentiated human primary airway epithelial cells, a gold standard for the pre-clinical evaluation of patients' responsiveness to pharmacological treatments. This new combinatory approach also leads to an improvement in CFTR conductance on cells expressing other rare CF-causing mutations, including N1303K, for which Trikafta is not approved. These findings show that Trikafta therapy can be improved by the addition of a drug targeting the misfolding detection machinery at the beginning of the ubiquitination cascade and may pave the way for an extension of Trikafta to low/non-responding rare misfolded CFTR mutants.
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