The role of sweat chloride in determining CFTR protein restoration in people with cystic fibrosis.

Real-life application of the Optical Beta-Adrenergic Sweat Test for people with cystic fibrosis.

Cystic fibrosis (CF) has become increasingly treatable with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-targeted therapies. However, the availability and efficacy of these treatments depend on each patient's CFTR genotype, necessitating careful follow-up to detect effective benefits. This study builds on our previous findings by applying the Optical Beta-Adrenergic Sweat Test (OBAST) as a complement to the classical sweat Cl- testing (ST) to better evaluate the restoration of CFTR activity in vivo. We quantified the sweat droplet number (SDN) and the ratio between CFTR-dependent (beta-adrenergic Cocktail-induced, C-phase) and the CFTR-independent (Methacholine-induced, M-phase) sweat rates (C/M ratio) in 128 non-CF subjects and 143 people with CF (PwCF). Among the PwCF, 39 were treated with various combinations of the CFTR modulators, including Lumacaftor/Ivacaftor (LI), Tezacaftor/Ivacaftor (TI) and/or Elexacaftor/Tezacaftor/Ivacaftor (ETI). SDN detected an earlier response to CFTR modulators, yielding lower p-values than the C/M rate ratio, particularly during ETI therapy. Thus, SDN counting provides a simpler and faster method than C/M ratio for monitoring the effects of CFTR modulators on CFTR function, without compromising sensitivity or reliability. This enables more precise tracking of drug efficacy in individual subjects. In six PwCF, who underwent at least two different CFTR-targeted therapies, we also assessed lung function and nasal potential difference (NPD) in addition to ST, SDN, and the C/M ratio. We propose OBAST as a reliable complementary tool to standard tests, especially valuable when CFTR-targeted drugs are not approved for rare CFTR genotypes, when clinical response appears limited, and/or when sweat [Cl-] results are inconclusive.

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.

Residual disease activity in cystic fibrosis lung disease: implications for clinical management and research.

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.

Clinical benefit without sweat chloride response after ETI therapy in an adult with cystic fibrosis bearing the L467F;F508del complex CFTR allele: a case report and the role of AI-assisted chest CT in longitudinal monitoring

Elexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. However, predicting responses to CFTR modulators in rare or complex CFTR genotypes is challenging. Sweat chloride concentration (SCC) and patient-derived functional assays assessing CFTR-mediated chloride transport are commonly used to classify modulator responsiveness. Carriers of the p.Leu467Phe;p.Phe508del (henceforward legacy nomenclature: L467F;F508del) complex CFTR allele have been considered unlikely to respond to ETI, based on short-term clinical, biomarker and ex vivo evidence. We report a discordant long-term response in an adult carrying this complex allele, with clinically meaningful benefit despite persistently negative CFTR chloride transport biomarkers. We describe an 8-year longitudinal pre- and post-treatment assessment of an adult woman with CF, adherent to therapy, with the L467F;F508del complex allele compounded with the non-responsive c.489 + 1G > T (621 + 1G > T) variant in trans . She has pancreatic insufficiency, progressive lung disease, and recurrent pulmonary exacerbations. After ETI commencement (at 40.5 years; July 2021) SCC remained unchanged at ∼100 mmol/L. Intestinal organoid and primary nasal epithelial cell assays showed no measurable ETI-related CFTR-mediated chloride transport rescue. Nevertheless, BMI increased from 22.0 to 26.8 kg/m 2 , annual exacerbations decreased from 5 to 3, and ppFEV₁ improved from 51% to 55–59%. Serial chest CT showed a shift from pre-ETI progression to post-ETI stabilisation, with reductions in air trapping and the extent of bronchiectasis on manual Brody II scoring and LungQ/PRAGMA-AI quantification. Exploratory in vitro exposure of nasal epithelial cells to vanzacaftor/tezacaftor/ivacaftor yielded ∼5% CFTR-mediated rescue, contrasting with the negative ETI response. Persistent CFTR biomarker negativity may not fully exclude clinically meaningful ETI-associated benefit in rare or complex CFTR genotypes. The pulmonary and extrapulmonary improvements observed in this case support multidimensional response assessment beyond single-biomarker endpoints. These hypothesis-generating observations support individualised long-term monitoring and comprehensive interpretation of CFTR biomarkers in the clinical context. AI-assisted chest CT may provide complementary real-world evidence. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles.

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.

Pediatric cystic fibrosis is associated with type 3 immune response