ArticleAmerican journal of respiratory cell and molecular biology2014
Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor.
Article in American journal of respiratory cell and molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 149 citations in OpenAlex.
- Phase 1 Renal Impairment Trial Results Supports Targeted Individualized Dosing of ELX-02 in Patients With Nephropathic Cystinosis.Journal of clinical pharmacology · 2021Trial
- Ivacaftor in People with Cystic Fibrosis and aAnnals of the American Thoracic Society · 2021Trial
- Identification of small molecules that enhance aminoglycoside-mediated suppression ofMolecular therapy. Oncology · 2026Article
- RFFL-mediated protein quality control limits functional rescue of TRID-CFTR modulator combination therapy for cystic fibrosis nonsense mutations.Cellular and molecular life sciences : CMLS · 2026Article
- A Translational Roadmap for Neurological Nonsense Mutation Disorders.International journal of molecular sciences · 2026Review
- Identity, functional consequences, and context effects of amino acids inserted during suppression of CFTR nonsense mutations.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2026Article
- Clinical and genetic characteristics of diseases caused by CFTR gene mutations in 15 Chinese children: a retrospective analysis.BMC pediatrics · 2025Article
- A W1282X cystic fibrosis mouse allows the study of pharmacological and gene-editing therapeutics to restore CFTR function.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2025Article
- Differential distribution of ivacaftor and its metabolites in plasma and human airway epithelia.Pulmonary pharmacology & therapeutics · 2024Article
- mRNA-specific readthrough of nonsense codons by antisense oligonucleotides (R-ASOs).Nucleic acids research · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.Biomedicines · 2024Review
- Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations.Nature communications · 2024Article
- Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.Cell stem cell · 2024Article
- Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X.Human molecular genetics · 2023Article
- Nonsense mutation suppression is enhanced by targeting different stages of the protein synthesis process.PLoS biology · 2023Article
- The synthetic aminoglycoside ELX-02 induces readthrough of G550X-CFTR producing superfunctional protein that can be further enhanced by CFTR modulators.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine.Cell death & disease · 2022Article
- Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia.International journal of molecular sciences · 2022Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 4 institutions in 3 countries.
Funding
Abstract
New drugs are needed to enhance premature termination codon (PTC) suppression to treat the underlying cause of cystic fibrosis (CF) and other diseases caused by nonsense mutations. We tested new synthetic aminoglycoside derivatives expressly developed for PTC suppression in a series of complementary CF models. Using a dual-luciferase reporter system containing the four most prevalent CF transmembrane conductance regulator (CFTR) nonsense mutations (G542X, R553X, R1162X, and W1282X) within their local sequence contexts (the three codons on either side of the PTC), we found that NB124 promoted the most readthrough of G542X, R1162X, and W1282X PTCs. NB124 also restored full-length CFTR expression and chloride transport in Fischer rat thyroid cells stably transduced with a CFTR-G542XcDNA transgene, and was superior to gentamicin and other aminoglycosides tested. NB124 restored CFTR function to roughly 7% of wild-type activity in primary human bronchial epithelial (HBE) CF cells (G542X/delF508), a highly relevant preclinical model with endogenous CFTR expression. Efficacy was further enhanced by addition of the CFTR potentiator, ivacaftor (VX-770), to airway cells expressing CFTR PTCs. NB124 treatment rescued CFTR function in a CF mouse model expressing a human CFTR-G542X transgene; efficacy was superior to gentamicin and exhibited favorable pharmacokinetic properties, suggesting that in vitro results translated to clinical benefit in vivo. NB124 was also less cytotoxic than gentamicin in a tissue-based model for ototoxicity. These results provide evidence that NB124 and other synthetic aminoglycosides provide a 10-fold improvement in therapeutic index over gentamicin and other first-generation aminoglycosides, providing a promising treatment for a wide array of CFTR nonsense mutations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.