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

Abstract Purpose Pathogenic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene result in dysfunctions of the 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 (HEMTs), such as the Elexacaftor–Tezacaftor–Ivacaftor (ETI) combination, may represent the primary therapeutic option for approximately 82% of people with cystic fibrosis (pwCF) who have at least one F508del variant. However, the remaining 18% with rare CFTR variants, including nonsense variants, often lack access to these therapies. Nonsense variants lead to non-functional 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 (PDIOs) to evaluate the recovery of CFTR function in cells with nonsense variants. Results Specifically, we tested three translational readthrough-inducing molecules: NV848, NV914, and NV930. Our studies highlighted the positive effect of NV848 on patient organoid swelling, improving CFTR channel function, while NV914 and NV930 didn’t induce organoid swelling, similarly to PTC124 treatment. Conclusion In conclusion, this study highlights the potential of translational readthrough-inducing molecules to restore CFTR function in cells with nonsense variants. By leveraging patient-derived intestinal organoids, our findings showed that NV848, in combination with ETI and the NMD 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.