Aug 2026· Respiratory care· pp.
19433654261477809
· 0 citations· 4 references
Medicine
TL;DR
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.
Abstract
The introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has transformed the therapeutic landscape of cystic fibrosis. CFTR modulators target specific functional defects in the CFTR protein, improving its folding, trafficking, gating, or conductance depending on mutation class. As CFTR modulators become the standard of care, emerging data highlight not only their transformative benefits but also knowledge gaps regarding long-term outcomes, variability in therapeutic response, effects on early disease, and extra-pulmonary implications for people with cystic fibrosis (CF) complications. Additionally, access, tolerability, and the needs of individuals with rare or non-modulator-responsive mutations remain important challenges. This article aims to provide a summary of recent literature pertaining to CFTR modulators. Through this summary, we seek 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.
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.
Sara Allushi, M. Virgulti, Giovanna Blaconà et al.· International Journal of Mol...· 0 citations
The advent of CFTR modulators is fundamentally reshaping people with cystic fibrosis (pwCF) care and research. Despite unprecedented improvements in lung function and predicted survival, a substantial proportion of pwCF continue to exhibit residual disease activity (RDA) across multiple biological and clinical domains. Persistent abnormalities in CFTR function, mucus properties, mucociliary clearance, airway infection, inflammation and symptom burden indicate that CFTR modulation does not fully normalize airway physiology or eliminate the pathological processes underlying CF lung disease. This review proposes RDA as a conceptual framework for identifying ongoing, potentially modifiable disease processes in people receiving CFTR modulators. Candidate measures across complementary mechanistic and clinical domains are examined, and their potential multidimensional interpretation as a means of supporting more individualized monitoring and treatment decisions is discussed. We consider the implications of RDA for clinical research by identifying key evidence gaps, outlining a stepwise pathway for its definition and validation. We further explore the potential to inform sensitive endpoint selection, enrich study populations and guide the development of therapies targeting disease processes that persist despite CFTR modulation. As the CF population ages and disease trajectories evolve, care models and research priorities must move beyond conventional measures of disease severity alone. A better understanding and systematic evaluation of RDA may help align long-term clinical management and future trial design with the changing needs of people with CF, while ensuring that therapeutic advances translate into sustained health gains.
A. Gramegna, G. Putti, Gianfranco Alicandro et al.· American Journal of Respirat...· 0 citations
It is concluded that childhood CF is being transformed rather than solved, and that surveillance, nutritional and psychosocial frameworks developed in the pre-modulator era require deliberate re-evaluation rather than uncritical continuation.
S. Bittmann, E. Luchter, E. Moschüring-Alieva· Asian Journal of Pediatric R...· 0 citations
Sweat chloride concentrations are elevated in people with cystic fibrosis due to the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial cell membrane ion channel. For many people with cystic fibrosis with responsive variants and drug access, treatment with CFTR modulators increases CFTR function, reduces sweat chloride concentrations, and improves lung health and quality of life. In clinical trials, average sweat chloride reduction is correlated with clinical efficacy across different modulators and study populations. Thus, for people with cystic fibrosis, larger reductions and lower absolute sweat chloride concentrations are often presumed to indicate greater clinical response and better prognosis. However, although true at the population level, at the individual level, a relationship between sweat chloride and clinical outcomes has not been definitively shown. This Personal View highlights how sweat chloride quantification informs our understanding of CFTR modulator therapeutic response while cautioning its ability to fully predict individual clinical response.
E. T. Zemanick, S. Graeber, Carlo Castellani et al.· The Lancet Respiratory Medic...· 0 citations
A potential combination between gene therapy approaches and existing modulators to improve treatment eligibility, safety, and efficacy for cystic fibrosis patients is discussed.
The available data show a signficant progress in the availability of pathogen-oriented therapy in the SFD, but there remain genetic, age-related, and institutional barriers limiting full patient coverage with highly effective CFTR-modulators.
V. Brisin, A. E. Kidakoeva, S. Trishina et al.· Meditsinskiy sovet = Medical...· 0 citations
Related blog posts
MIT News · Artificial Intelligence· news.mit.eduAug 27, 2026
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
