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
Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disorder among populations of European ancestry, and the childhood years determine much of its long-term trajectory. The therapeutic landscape has been reshaped by cystic fibrosis transmembrane conductance regulator (CFTR) modulators, yet the paediatric evidence base has matured unevenly across the domains that matter most to affected children. This critical narrative review evaluates the strength, consistency and limitations of the literature on CF in childhood, spanning pathophysiology, newborn screening and diagnosis, early airway infection and structural lung disease, nutrition and gastrointestinal involvement, CF-related diabetes, CFTR modulator therapy, and mental health. Peer-reviewed studies, professional consensus guidelines and authoritative institutional sources were appraised for methodological quality and translated into a thematic synthesis rather than a study-by-study catalogue. The evidence most strongly supports early diagnosis through newborn screening, the predictive value of early neutrophilic inflammation and infection for structural lung disease, and the short-to-medium-term efficacy and tolerability of triple CFTR modulator therapy in children as young as two years. Confidence is weaker for long-term safety, for outcomes in children ineligible for or unable to access modulators, and for the neuropsychiatric effects attributed to these drugs, where observational signals and case reports remain difficult to disentangle from the psychological burden of chronic illness. Persistent gaps include the management of inconclusive screening results, the durability of modulator benefit initiated in early life, the evolving natural history of CF-related diabetes and pancreatic disease under modulator therapy, and equity of access across health systems. The review concludes 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
Since the development of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator in 2012, these therapies have revolutionized patients’ health. They are now the most effective treatment for people with cystic fibrosis (pwCF). In fact, elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor, the latest combination therapies consisting of a CFTR potentiator and two CFTR correctors, improved lung function by 14% in pwCF. Other modulator therapies targeting CFTR mRNA and/or protein are currently under preclinical/clinical investigation. However, due to the variant-specific nature of these therapies, about 10% of pwCF in Europe remains without effective treatment, and many treated pwCF experience various adverse events such as headaches, infections, hepatotoxicity, hypertension, and depression. Therefore, mutation-agnostic strategies such as gene therapy are needed. They could expand treatment eligibility for all pwCF and improve outcomes. In fact, nucleic acid delivery (e.g., pDNA, mRNA, oligonucleotides, genome editing) or targeting non-CFTR channels to restore ion transport represent promising future additional directions for CF therapy. This review aims to discuss a potential combination between gene therapy approaches and existing modulators to improve treatment eligibility, safety, and efficacy.
Introduction
. Cystic fibrosis (CF) remains one of the most significant inherited multisystem diseases of childhood, characterized by progressive damage to the bronchopulmonary system, exocrine pancreatic insufficiency, and marked clinical phenotype variability governed by both underlying genotype and the timing of pathogenetic therapy initiation. Recently, the advent of CFTR-modulators dramatically changed the paradigm of CF management, as it has become possible for the first time to address the molecular defect underlying the disease, rather than just its clinical manifestations.
Aim
. To analyze the regional structure of the CF patient population in the Southern Federal District (SFD) and assess the coverage of the pediatric cohort with targeted therapy.
Materials and methods
. A descriptive analysis was conducted using the regional data on CF patients in the SFD. The following parameters were assessed: the number of patients, patient distribution across the SFD entities, the number of newly diagnosed cases in 2025, the volume of patient referrals to the therapeutic facilities, availability of CFTR-modulators, and prescription profiles.
Results
. The SFD CF population was estimated at 521 patients, with 366 children and 155 adults. The Krasnodar Territory, Rostov Region, Republic of Crimea, and Volgograd Region had the largest cohorts of CF patients. In 2025, 20 new cases of the disease were diagnosed in the district, as compared with the expected number of 25–30, calculated from population-based data on the average incidence of CF in the Russian Federation. 246 children received targeted therapy, while 120 patients remained without pathogen-oriented treatment. Among targeted drugs dominated the triple combination composed of elexacaftor, tezacaftor, and ivacaftor introduced to the Russian market under the trade name Trilexa® (Tuteur S.A.C.I.F.I.A., Argentina) (78%) and Trikafta® (Vertex Pharmaceuticals) (15.9%).
Conclusions.
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. The regional analysis highlights the need for further improvements in the neonatal screening system, expansion of genotypeoriented therapy, and continuity of medical care for adolescents and young adults.
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.