Combining Gene Therapy with Current Modulator Treatments for Cystic Fibrosis: A Promising Area of Research

Targeted Therapy for Restoring CFTR Activity: From Experimental to Clinical Features

Cystic fibrosis (CF) is one of the most common rare genetic diseases. It is caused by pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. More than 2200 variants have been identified in the CFTR gene that need detailed knowledge and functional characterization in order to develop specific therapeutic strategies. The traditional therapy for CF relied on addressing symptoms through mucolytic and antibiotic treatments, respiratory physiotherapy and aerosol therapy. However, in the last few years, the development of small new molecules targeting and restoring the underlying CFTR channel defect marked an important step in CF treatment. In addition, the implementation of patient-specific cellular models allowed the evaluation of pharmacological responses, leading to therapeutic advances in the direction of personalized treatment. The focus of this review is to describe and discuss the strategies for restoring the CFTR functional defects depending on the specific CFTR pathogenic variants. In particular, the review highlights the possible application of experimental and clinical drugs to CF treatment, which may allow improvements in patients’ quality of life and life expectancy. The in vitro testing of therapeutic drugs (theratyping) is performed nowadays through the use of several cellular models, especially those derived from patient-specific tissues. This topic is a hot point in CF research and the review also aims to provide an overview of the state of the art in theratyping. The novelty of this review is the integrated view of the most recent achievements in precision diagnostics and therapy of CF at the molecular, cellular and clinical level, which are able to change the natural history of this disease.

Year in Review: Cystic Fibrosis Modulator Therapy-Efficacy, Access, and Evolution.

A summary of recent literature pertaining to CFTR modulators is provided to enhance the knowledge of the growing body of evidence guiding the next era of CF care, in which disease modification at the molecular level is increasingly achievable.

Efficacy and safety of pathogenetic therapy for cystic fibrosis in children in the Chechen Republic: Use of a generic CFTR modulator and experience of switching within a same international non-proprietary name

Introduction . Cystic fibrosis is a hereditary disease associated with progressive damage to the bronchopulmonary system and the risk of disability. The introduction of triple CFTR modulators (ivacaftor/tezacaftor/elexaftor and ivacaftor) has significantly improved the prognosis. However, the high cost of the original drug Trikafta® and limited healthcare resources have driven interest in the bioequivalent generic drug Trilexa®. Aim . To evaluate the efficacy and safety of the pathogenetic therapy drugs Trikafta and Trilexa in children with cystic fibrosis in the Chechen Republic, as well as the transition from the original to the generic version within the same INN (ivacaftor + tezacaftor + elexacaftor and ivacaftor), in routine clinical practice. Materials and methods . A retrospective, single-center observational study was conducted in the Chechen Republic. The analysis included 22 patients under 18 years of age with a genotype corresponding to the indications for triple CFTR modulator therapy. Three groups were formed: Group 1 (n = 5) – treatment with Trikafta only; Group 2 (n = 2) – treatment with Trilexa only; Group 3 (n = 15) – patients switched from Trikafta to Trilexa. Changes in sweat chloride concentrations, body mass index (BMI), pulmonary function parameters (FEV₁, FVC), the frequency of pulmonary exacerbations, and the safety profile were assessed. Results . A decrease in sweat chloride concentrations was noted in all groups, indicating restoration of CFTR function. In Group 3, sweat chloride levels decreased from 91.0 to 41.0 mmol/L while on Trikafta and remained stable after switching to Trilexa. BMI significantly increased from 14.9 to 15.7 kg/m² during the Trikafta phase (p = 0.002) and continued to increase after switching to Trilexa. FEV₁ and FVC remained consistently high after switching (p > 0.05). The incidence of pulmonary exacerbations decreased and remained minimal while on Trilexa. Conclusion. The use of both the original drug and generic Trilexa in children with CF is associated with clinical improvements in key efficacy indicators and a favorable safety profile.

Gene therapy for rare diseases marks a new era in precision medicine: Insights from clinical trials

Clinical evidence suggests that gene-based therapies in the management of rare diseases can achieve sustained functional benefits, reduce disease-related complications, and lessen dependence on long-term replacement or supportive treatments.

Case Report: When access is limited: using CYP3A4 inhibition to maintain clinical benefit from elexacaftor/tezacaftor/ivacaftor

Introduction Cystic fibrosis transmembrane conductance regulator modulators (CFTRm), particularly elexacaftor/tezacaftor/ivacaftor (ETI), have transformed outcomes for people with cystic fibrosis (pwCF). However, access remains limited globally due to genotype-based eligibility and high medication cost. Pharmacokinetic manipulation using cytochrome P450 3A4 (CYP3A4) inhibitors has emerged as a potential strategy to extend ETI exposure in resource-constrained settings. Case We describe a 52-year-old female with CF (G542X/T1246I) whose genotype initially precluded subsidised ETI access in Australia. She experienced progressive clinical decline in 2024, with worsening bronchiectasis, recurrent Pseudomonas aeruginosa exacerbations, and a fall in ppFEV1 below 40%. Supported by in vitro evidence of T1246I responsiveness, she self-funded ETI, resulting in rapid symptomatic improvement, reduced sputum burden, and objective gains in lung function, sweat chloride, and weight. To improve affordability, azithromycin was replaced with clarithromycin, a potent CYP3A4 inhibitor, enabling a reduced ETI dosing schedule. Therapeutic drug monitoring demonstrated lower serum concentrations of all ETI components compared with full-dose therapy, yet clinical stability and improved quality of life were maintained, with no further exacerbations. Clarithromycin was selected due to its established safety profile and dual utility as macrolide therapy, avoiding the hepatotoxicity risk associated with azole antifungals. Conclusion This report supports the potential for CYP3A4 inhibition to aid with personalised ETI dosing strategies, particularly in low and middle-income countries where CFTRm access remains limited. Further research is needed to define optimal manipulation strategies, understand inter-individual variability in CFTRm metabolism, and evaluate the feasibility of therapeutic drug monitoring in diverse healthcare settings.

Gene Therapy in Heart Failure: A Systematic Review of Therapeutic Potential, Limitations, and Future Directions