CFTR rescue in W1282X cystic fibrosis patient-derived intestinal organoids (PDIOs) mediated by translational readthrough-inducing drugs (TRIDs)

Sep 29, 2026

Pathogenic variants in the CFTR gene cause cystic fibrosis (CF) by disrupting CFTR function, leading to severe respiratory and digestive symptoms. Highly effective CFTR modulators can treat many patients with at least one F508del variant, yet individuals with rare CFTR variants, particularly nonsense variants, often remain without access to these therapies. This study uses patient-derived intestinal organoids to assess CFTR function recovery with translational readthrough-inducing drugs and associated inhibitor strategies.

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CategoryHealthcare

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Introduction

Article info and abstract overview

Introduction: organoid model and patient relevance

Genetics in Medicine Open (2026) 4, 103472 [www.journals.elsevier.com/genetics-in-medicine-open](www.journals.elsevier.com/genetics-in-medicine-open) ARTICLE CFTR rescue in W1282X cystic fibrosis patient-derived intestinal organoids (PDIOs) mediated by translational readthrough-inducing drugs (TRIDs) Riccardo Perriera 1, 2, Anabela S. Ramalho3, Francois Vermeulen3,4, Emanuele Vitale 1, Ivana Pibiri 1, *, Andrea Pace1 , Laura Lentini 1, * 1Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy; 2Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo, Italy; 3Department of Development and Regeneration, Woman and Child Unit, CF research lab, KU Leuven, Leuven, Belgium; 4Department of Pediatrics, Pediatric Pulmonology, UZ Leuven, Leuven, Belgium | ARTICLE INFO | ABSTRACT | | --- | --- | | Article history:
Received 28 March 2025
Received in revised form
4 November 2025
Accepted 6 November 2025 Available online 17 November 2025 | Purpose: Pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in dysfunctionsofthe CFTR protein, leading to cystic fibrosis (CF). This genetic disorder is characterized by severe symptoms in the respiratory and digestive systems.Currently, highly effective CFTR modulator treatments, such as the Elexacaftor-Tezacaftor-Ivacaftor combination, may represent the primary therapeutic option for approximately 82% of people with cystic fibrosis who have at least 1 F508del variant. However, the remaining 18% with rare CFTR variants, including nonsense variants, often lack access to these therapies. Nonsense variants lead to nonfunctional CFTR proteins and contribute to more severe CF symptoms. Research efforts focus on understanding the effects of these variants on disease severity and response to treatment. Methods: This study utilizes patient-derived intestinal organoids to evaluate the recovery of CFTR function in cells with nonsense variants.
Results: Specifically, we tested 3 translational readthrough-inducing molecules: NV848, NV914, and NV930 . Our studies highlighted the positive effect of NV848 on patient organoid swelling, improving CFTR channel function, whereas NV914 and NV930 did not induce organoid swelling, similar to PTC124 treatment.
Conclusion: In conclusion, this study highlights the potential of translational readthroughinducing molecules to restore CFTR function in cells with nonsense variants. By leveraging patient-derived intestinal organoids, our findings showed that NV848, in combination with Elexacaftor-Tezacaftor-Ivacaftor and the nonsense-mediated mRNA decay inhibitor NMDI14, enhances CFTR activity. This contributes to the development of personalized therapies for individuals with rare CFTR variants, addressing a critical unmet need in cystic fibrosis treatment. | | Keywords:
CFTR
Cystic fibrosis Intestinal organoids Nonsense variants Translational readthrough | | The Article Publishing Charge (APC) for this article was paid by Laura Lentini, Ivana Pibiri. *Correspondence and requests for materials should be addressed to Ivana Pibiri, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Parco d'Orleans-viale delle Scienze, 90128 University of Palermo, Palermo, Italy. Email address: [ivana.pibiri@unipa.it](ivana.pibiri@unipa.it) OR Laura Lentini, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Parco d'Orleans-viale delle Scienze, 90128 University of Palermo, Palermo, Italy. Email address: [laura.lentini@unipa.it](laura.lentini@unipa.it) doi: [https://doi.org/10.1016/j.gimo.2025.103472](https://doi.org/10.1016/j.gimo.2025.103472) 2949-7744/© 2025 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license ([http:

FAQs

What is the main therapeutic problem addressed in the study?

Nonsense CFTR variants produce nonfunctional CFTR proteins, leaving a subset of patients with limited access to standard highly effective CFTR modulator therapies.

What experimental system does the study use?

Patient-derived intestinal organoids (PDIOs) are used to evaluate recovery of CFTR function in cells carrying nonsense variants.

Which translational readthrough-inducing molecules were tested, and what was the key finding?

NV848, NV914, and NV930 were tested; NV848 improved organoid swelling and CFTR channel function, while NV914 and NV930 did not induce swelling similarly to PTC124.

Sep 29, 2026

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