Journal of Cystic Fibrosis最新文献

{"title":"WS01.01Predicting future pulmonary exacerbation (PEx) rates for cystic fibrosis (CF) clinical trials","authors":"D. VanDevanter ,&nbsp;C. O'Rourke ,&nbsp;K. Odem-Davis ,&nbsp;J. Clancy ,&nbsp;M. Konstan ,&nbsp;N. Mayer Hamblett","doi":"10.1016/j.jcf.2025.03.492","DOIUrl":"10.1016/j.jcf.2025.03.492","url":null,"abstract":"<div><h3>Objectives</h3><div>Due to the clinical importance of CF pulmonary exacerbations (PEx), regulators accept PEx rate difference as clinical trial efficacy endpoint. Although CFTR modulators have reduced overall PEx rates, this endpoint remains relevant to future CF drug development, provided study populations can be enriched for individuals with elevated PEx risk. Although the number of prior-year PEx treated with intravenous antimicrobials (IV-PEx) strongly predicts future IV-PEx risk [JCF. 2016;15(3):372-9], IV-PEx incidence has fallen to a point where it has little if any utility as a clinical trial endpoint: today PEx treated with antibiotics <em>by any route</em> (anyPEx) are studied despite little knowledge of associations between prior year anyPEx number and future PEx rates. We tested whether prior year anyPEX number predicted future anyPEx rates in CF adults receiving and not receiving the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI).</div></div><div><h3>Methods</h3><div>CF adults with data present in the CF Foundation Patient Registry (CFFPR) in 2022 &amp; 2023 were studied, provided they had received either</div><div>a) ETI or</div><div>b) no modulators in both years.</div><div>AnyPEx were counted; treatments starting &lt;28 days of a previous treatment start were considered part of the previous PEx. 2023 PEx rates were compared among subgroups having 0, 1-2, or 3+ PEx in 2022.</div></div><div><h3>Results</h3><div>PEx counted in 2022 strongly correlated with mean 2023 PEx rates within both the ETI and No Modulator groups (P&lt;.001, table), with the mean rate for the entire ETI group lower than that of the No Modulator group, as well as within subgroups with <u>0 and 1-2 PEx</u> in 2022 (table).<span><div><div><table><thead><tr><td><span>Empty Cell</span></td><th>No 2022 PEx</th><th>One or Two 2022 PEx</th><th>Three plus 2022 PEx</th><th>Overall</th></tr></thead><tbody><tr><th><strong>2023 ETI group PEx rate (N)</strong></th><td>0.23/yr (9452)</td><td>0.78/yr (3267)</td><td>2.19/yr (469)</td><td>0.43/yr (13,188)</td></tr><tr><th><strong>2023 No Modulator group PEx rate (N)</strong></th><td>0.32/yr (1356)</td><td>1.08/yr (633)</td><td>2.37/yr (159)</td><td>0.70/yr (2148)</td></tr><tr><th><strong>Relative rate (ETI/No Modulator), [95% CI]</strong></th><td>0.71 [0.63, 0.79]</td><td>0.72 [0.65, 0.80]</td><td>0.92 [0.78, 1.10]</td><td>0.62 [0.57, 0.68]</td></tr></tbody></table></div></div></span></div></div><div><h3>Conclusions</h3><div>An unmet need for therapeutic interventions to reduce CF PEx risk remains, even in populations receiving CFTR modulators. The number of anyPEx counted in a prior year strongly predict future anyPEx rates in adults, suggesting an enrichment approach for CF trials using difference in PEx rates as an efficacy endpoint.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S1"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS14.01Primary nasal epithelial cells for personalized medicine in non-eligible cystic fibrosis patients","authors":"J. Berger ,&nbsp;A. Balázs ,&nbsp;T. Rubil ,&nbsp;A. Gonzáles ,&nbsp;J. Berges ,&nbsp;Y. Yu ,&nbsp;O. Sommerburg ,&nbsp;M. Stahl ,&nbsp;M.A. Mall ,&nbsp;S.Y. Graeber","doi":"10.1016/j.jcf.2025.03.570","DOIUrl":"10.1016/j.jcf.2025.03.570","url":null,"abstract":"<div><h3>Objective</h3><div>Patients with cystic fibrosis (pwCF) without any <em>F508del</em> allele in the cystic fibrosis transmembrane conductance regulator (<em>CFTR</em>) have currently no access to CFTR modulator therapy in Europe. To test the potential of pharmacological rescue of CFTR by ETI in non-eligible pwCF, we tested the <em>in vitro</em> and <em>in vivo</em> effects of ETI in non-<em>F508del</em> pwCF.</div></div><div><h3>Methods</h3><div>Highly differentiated primary human nasal epithelial cultures (pHNECs) were cultivated from nasal swabs of 39 pwCF and non-<em>F508del CFTR</em> mutations and 29 healthy controls. CFTR activity was assessed by short-circuit currents in non-perfused Ussing chamber after ETI or DMSO incubation. In 10 pwCF, who received ETI therapy after a preclinical response in pHNECs, we assessed lung function (FEV₁% predicted) and the <em>in vivo</em> CFTR biomarkers sweat chloride concentration (SCC) and intestinal current measurements (ICM) or nasal potential difference (NPD) at baseline and 1 to 3 months after ETI.</div></div><div><h3>Results</h3><div>Twenty-five pwCF showed no increased CFTR activity in pHNECs after treatment with ETI compared to DMSO. However, pHNECs from 14 pwCF showed a response to ETI with a mean correction of CFTR activity of 20% of the healthy level. The 10 pwCF who received ETI showed a mean improvement in FEV₁% predicted by 12%. All 10 pwCF showed a pathological SCC above 60 mmol/L, which was reduced by at least 5 mmol/L after ETI. In ICM, the cAMP-dependent chloride secretory response increased from -12 µA/cm² to 32 µA/cm² after ETI and the total chloride secretory response increased from -16 µA/cm² to 123 µA/cm². A subgroup of 6 pwCF, where NPD was performed, showed an increase in total chloride response in NPD from -0.25 mV to -14 mV after ETI.</div></div><div><h3>Conclusion</h3><div>We identified non-<em>F508del CFTR</em> mutations responding to ETI <em>in vitro</em> with improvements in FEV₁%, SSC, ICM, and NPD. Our data show that <em>in vitro</em> CFTR modulator testing in pHNECs, confirmed by <em>in vivo</em> biomarkers, is a promising approach for personalized medicine in non-eligible pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S27"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS13.04Management of intermediate sweat chloride results and diagnosis of CFTR related disorders in a large tertiary paediatric centre","authors":"K. Rose ,&nbsp;C. Bradford ,&nbsp;A.F. Robson ,&nbsp;L. Tetlow ,&nbsp;B. Hird ,&nbsp;A. Shawcross","doi":"10.1016/j.jcf.2025.03.567","DOIUrl":"10.1016/j.jcf.2025.03.567","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to review the management of children and young people who have had a sweat test with a sweat chloride concentration (SCC) in the intermediate range between 30 and 59mmol/L.</div></div><div><h3>Methods</h3><div>All sweat tests with a result in the intermediate range undertaken at our large tertiary paediatric hospital between 01/01/2019 and 31/12/2023 were identified from laboratory records. Electronic health records were reviewed retrospectively to obtain further patient data. Patients diagnosed with CF or CF SPID following newborn screening were excluded.</div></div><div><h3>Results</h3><div>A total of 47 patients were identified. The primary indication for performing a sweat test included chronic respiratory concerns (74%), pancreatitis (6%), poor growth (6%), surgical concerns (rectal prolapse, bowel stricture - 4%), gastrointestinal symptoms (4%) and nasal polyps (4%).</div><div>A total of 31 patients (66%) underwent genetic testing. Five patients were found to have two <em>CFTR</em> mutations, in each case one known to be CF causing and one variant of varying clinical consequence. Four were heterozygous for one CF causing mutation. Eight patients (17%) had not been seen by a CF physician. Only 14 patients had documented advice on CFTR dysfunction.</div></div><div><h3>Conclusions</h3><div>In our large paediatric centre we identified a significant number of patients with an intermediate SCC who had not received further genetic investigations. There were also a number in whom documented advice on CFTR dysfunction had not been provided and a group who had not been reviewed by the CF team. In the era of modulator therapies and their potential clinical benefit, accurate diagnosis of CFTR related disorders is increasingly important. This work, along with the 2022 publication ‘ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria’ (Castellani, JCF 2022) will be used to define a new local guideline for referral of all patients with intermediate SCC to clinicians with expertise in CF diagnosis.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S26-S27"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS04.02Gut microbiota-metabolome relationships across CFTR modulator usage: preliminary findings from the GRAMPUS-CF study","authors":"R. Marsh ,&nbsp;W. Cheung ,&nbsp;D. Arends ,&nbsp;D. Sills ,&nbsp;D.W. Rivett ,&nbsp;A.R. Smyth ,&nbsp;C. van der Gast","doi":"10.1016/j.jcf.2025.03.511","DOIUrl":"10.1016/j.jcf.2025.03.511","url":null,"abstract":"<div><h3>Objectives</h3><div>Despite shifts to highly effective CFTR modulators, some people with cystic fibrosis (pwCF) continue to experience intestinal abnormalities, associated symptoms, and gut microbiota dysbiosis. Baseline faecal samples across children and adults in the Gut Research Advancing a Mechanistic and Personalised Understanding of Symptoms in Cystic Fibrosis (GRAMPUS-CF) study were used to investigate relationships between gut microbiota composition and the intestinal metabolome under elexacaftor/tezacaftor/ivacaftor (ETI) treatment.</div></div><div><h3>Methods</h3><div>Gut microbiota profile was determined using PacBio full-length 16S HiFi sequencing (<em>n</em>=70). Untargeted metabolomics, including additional lipidomics, were performed with ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) (<em>n</em>=64). Correlation-based approaches were used to construct networks highlighting relationships between taxa and metabolites across paired samples. Participant clinical data was integrated to investigate associations with microbiota structure and function.</div></div><div><h3>Results</h3><div>A wide array of unique metabolites from the metabolomic (<em>n</em>=660) and lipidomic approaches (<em>n</em>=527) were identified from participant faecal samples. Network analyses highlighted both positive and negative associations across beneficial and potentially pathogenic taxa, extending to relationships with metabolites and lipids of physiological interest in the CF intestine. Clinical demographics also explained the variance observed across microbiota structure, alongside metabolomic and lipidomic profiles.</div></div><div><h3>Conclusions</h3><div>Faecal multi-omics indicate important relationships with gut microbiota structure across pwCF undertaking CFTR modulator therapy. Temporal dynamics of the gut microbiome across these participants will be investigated across ETI therapy in the GRAMPUS-CF study. Further clinical data, participant symptomatic data, and intestinal physiology metrics will support our future analyses.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S8"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS05.02CFTR mRNA delivery with a revolutionary non-LNP nanoemulsion formulation to differentiated primary human airway epithelium and airway organoid","authors":"K. Ito ,&nbsp;S. Hassibi ,&nbsp;Y. Yamamoto ,&nbsp;J. Shur ,&nbsp;G. Rapeport ,&nbsp;S. Sobolov","doi":"10.1016/j.jcf.2025.03.517","DOIUrl":"10.1016/j.jcf.2025.03.517","url":null,"abstract":"<div><h3>Objectives</h3><div>Cystic fibrosis (CF) is a progressive genetic disorder with impaired normal clearance of mucus due to the defect of a chloride channel, cystic fibrosis transmembrane regulator (CFTR). Currently approved CFTR modulators are applicable to limited genotypes and the universally applicable therapy would be functional CFTR protein expression by <em>CFTR</em> gene delivery. To address this challenge, RIGImmune has developed a non-LNP formulation delivery system, Nano-Emulsion Enhanced Delivery (NEED^TM) platform to deliver optimised CFTR encoded mRNA therapeutics.</div></div><div><h3>Methods</h3><div>Optimised <em>CFTR</em> mRNAs (Northern RNA, Canada) formulated with NEED^TM nanoemulsion system (RIG-301) were apically applied for up to 4 hrs to air-liquid interface (ALI) cultured differentiated human alveolar or bronchial epithelium (hAE or hBE, Epithelix) obtained from healthy subjects. Cells were collected at different timepoints up to 72hrs post-delivery, and CFTR protein was detected by western blotting. RIG-301 was also applied to human induced pluripotent stem cell (iPSC) derived CF ΔF508- airway organoids, and effects of forskolin-induced swelling were evaluated (HiLung Inc. Japan).</div></div><div><h3>Results</h3><div>RIG-301 nanoemulsion system (z-average particle size 176.9 nm) showed higher and long-lasting CFTR protein expression than naked CFTR mRNA delivery or delivered with jetPrime transfection reagent in hAE and hBE. In addition, RIG-301 showed an increased forskolin-induced swelling of CF-airway organoid, and the effects were comparable to or better than that of a triple combinations of CFTR modulators (VX-661/VX-445/VX-770: 3, 3 and 1 µM, respectively).</div></div><div><h3>Conclusion</h3><div>Our results demonstrate the capability of the NEED^TM platform to deliver optimised CFTR mRNA in ALI hAE and hBE cultures, as well as CF organoid. These preclinical data warrant further investigation of CFTR delivery and functional rescue in cells derived from CF patients.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS05.03Single administration of a lipid nanoparticle encapsulating HA-tagged CFTR mRNA to non-human primate lung results in expression of mRNA and protein in airway epithelium","authors":"J. Chen,&nbsp;M. El Khatib,&nbsp;G. Venkataraman,&nbsp;K. Srinivasan,&nbsp;J. Cefalu,&nbsp;S. Sherman,&nbsp;S. Katikaneni,&nbsp;S. Mohapatra,&nbsp;E. Hoxha,&nbsp;V. Kharitonov,&nbsp;B. Wustman,&nbsp;D. Ishimaru,&nbsp;J.A. Couch,&nbsp;D.J. Lockhart,&nbsp;M. Weinberg,&nbsp;H. Clark","doi":"10.1016/j.jcf.2025.03.518","DOIUrl":"10.1016/j.jcf.2025.03.518","url":null,"abstract":"<div><h3>Objectives</h3><div>Airway epithelial cells represent a key therapeutic target for the treatment of cystic fibrosis (CF), as abnormal CF <em>t</em>ransmembrane conductance regulator (CFTR) function in these cells drives the progression of lung disease in patients. The aim of the current study was to evaluate the cell-specific biodistribution and expression of a <em>CFTR</em> mRNA encapsulated in lipid nanoparticles (LNPs) upon delivery to the lungs of non-human primates.</div></div><div><h3>Methods</h3><div>Cynomolgus macaques (N=2 + 1 control) were anesthetized and delivered a HA-tagged human <em>CFTR</em> mRNA encapsulated in a ReCode Therapeutics LNP via intratracheal intubation in a nebulized aerosol. Lung tissues were harvested at 24h, digested and FAC-sorted in preparation for 10X single-cell RNA sequencing and transcriptomic analysis. Utilizing a custom bioinformatics and machine learning workflow, sorted cells with specific transcriptomic cell lineage signatures were evaluated for the presence of <em>HA-CFTR</em> mRNA. An immunohistochemistry (IHC) assay targeting the HA tag was developed to confirm the translational fidelity of the mRNA cargo.</div></div><div><h3>Results</h3><div>RNA isolated from EPCAM+ lung cells were analyzed using a UMAP dimensionality reduction on 10X Genomics scRNAseq sequencing data in the form of a cell-gene matrix to visualize the co-localization of <em>HA-CFTR</em> and various epithelial airway marker genes. A confirmatory machine learning model, trained on the Human Lung Atlas, was used to classify cell type and verify cell tropism. Data indicate presence of <em>HA-CFTR</em> mRNA in multiple sub-types of airway epithelial cells, including <em>SFTPB</em>+ ionocytes, <em>SCGB1A1</em>+ secretory cells, <em>AGER</em>+ AT Type 1 cells, and <em>SFTPC</em>+ AT Type 2 cells. IHC confirmed localization of the translated HA-tagged protein in secretory and basal airway cells.</div></div><div><h3>Conclusions</h3><div>Using a combinatory bioinformatic and spatial workflow, we show that dosing with LNP-<em>HA-CFTR</em> mRNA results in the delivery of nascent and translated cargo to key airway populations associated with CF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS05.04Comparison of preclinical and preliminary clinical safety profile of SPL84, an ASO for treatment of CF patients carrying the 3849 +10 Kb C -> T mutation, supporting an ongoing Phase 2 study","authors":"L. Friedman ,&nbsp;E. Ozeri-Galai ,&nbsp;A. Cohen ,&nbsp;G. Hart ,&nbsp;Y. Caraco ,&nbsp;M. Wanounou ,&nbsp;E. Kerem","doi":"10.1016/j.jcf.2025.03.519","DOIUrl":"10.1016/j.jcf.2025.03.519","url":null,"abstract":"<div><h3>Background</h3><div>SpliSense is developing SPL84, an inhaled ASO for the treatment of pwCF carrying the 3849 +10kb C-&gt;T (3849) mutation. SPL84 fully restored CFTR function in patient-derived HNEs and HBEs. Preclinical toxicology studies in mice and monkeys and a Phase 1 study in healthy volunteers (HVs) were conducted to support the ongoing Phase 2 study in 3849 pwCF.</div></div><div><h3>Methods</h3><div>In the preclinical toxicology studies, SPL84 was given via inhalation once a week for 9 weeks to mice and monkeys at dose levels of up to 54.4 mg/kg/week and 20.8 mg/kg/week, respectively. In the Phase 1 study, 32 subjects received a single inhaled dose of SPL84 at either 20, 40, 80, 160 mg or placebo (n=8 per cohort; 3:1 active:placebo). The primary objective was to evaluate the safety and tolerability of SPL84, and the secondary objective was to characterize the pharmacokinetics of SPL84.</div></div><div><h3>Results</h3><div>No SPL84-related clinical signs were observed in the preclinical toxicology studies. All of the microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled material. Systemic exposure in both species was low and the no observed adverse effect level for mice and monkeys was 54.4 and 20.8 mg/kg/week, respectively, which provided sufficient safety margins for the Phase 1 clinical doses.</div><div>SPL84 was well tolerated in the Phase 1 HV study, with no significant SPL84-related adverse events, and no significant effect on vital signs, clinical laboratory values, electrocardiogram, physical examination, or pulmonary function. Systemic exposure of SPL84 was low, as expected for an inhaled product, and tended to be dose dependent.</div></div><div><h3>Conclusions</h3><div>The safety and systemic exposure profile of SPL84 is similar across species (mice, monkeys, and humans). The preclinical and clinical safety profile of SPL84 is promising, with no clinical signs as well as low systemic exposure. This supported the initiation of an ongoing global Phase 2 study for the treatment of 3849 pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS09.03SLC26A9-mediated chloride transport is important for mucociliary clearance by healthy and cystic fibrosis airway epithelium","authors":"A. Balazs ,&nbsp;T. Rubil ,&nbsp;G.L. Harnisch ,&nbsp;C.K. Wong ,&nbsp;W. Namkung ,&nbsp;M. Drescher ,&nbsp;K. Seidel ,&nbsp;S.Y. Graeber ,&nbsp;M.A. Mall","doi":"10.1016/j.jcf.2025.03.542","DOIUrl":"10.1016/j.jcf.2025.03.542","url":null,"abstract":"<div><div>Genetic studies identified the solute carrier family 26 member 9 (<em>SLC26A9</em>) chloride transporter as a modifier of lung function in health and in cystic fibrosis (CF). Further, genetic deletion of <em>SLC26A9</em> in mice showed that SLC26A9–mediated chloride secretion is required to prevent mucus obstruction in type 2 airway inflammation. These data suggest that SLC26A9 is a promising therapeutic target in CF and potentially in other muco-obstructive lung diseases, however, its role in coordinated ion transport and mucociliary clearance in the human airways is not well understood. We generated human nasal epithelial (HNE) cultures from healthy donors and from patients with CF homozygous for either F508del or class I CFTR mutations to assess SLC26A9-mediated chloride secretion by short-circuit current measurements and to study the effect of pharmacological inhibition of SLC26A9 on mucociliary transport (MCT) velocity via time-lapse video microscopy. Inhibition with either S9-A13 or CFTRinh172 showed that SLC26A9 and CFTR contributed to basal (∆Isc=-0.55 µA/cm²; -1.74 µA/cm²) and cAMP-stimulated (∆Isc=-2.53 µA/cm²; -6.08 µA/cm²) chloride secretion in healthy HNE, whereas inhibition of both SLC26A9 and CFTR abolished transepithelial chloride secretion. Inhibition of SLC26A9 decreased MCT velocity (2.6 µm/s vs. 22.71 µm/s; p&lt;0.001) in healthy HNE. In CF cultures homozygous for F508del or class I mutations, residual chloride transport was predominantly mediated by SLC26A9. SLC26A9 inhibition decreased MCT velocity (1.85 µm/s vs. 14.87µm/s; p&lt;0.0001) in CF cultures. SLC26A9 and CFTR synergistically regulate transepithelial chloride secretion in healthy airway epithelia. In the CF airway epithelium SLC26A9 is important for residual chloride secretion and mucociliary transport, independent of the CFTR genotype. These findings support that SLC26A9 represents a promising therapeutic target to promote mucociliary clearance in CF and potentially in other muco-obstructive lung diseases.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S18"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS03.05What factors influence heart rate reserve in evaluating and prescribing exercise intensity for children and young people with CF?","authors":"E. Main ,&nbsp;W. Shirras ,&nbsp;N. Filipow ,&nbsp;H. Douglas ,&nbsp;E. Raywood ,&nbsp;S. Stanojevic","doi":"10.1016/j.jcf.2025.03.508","DOIUrl":"10.1016/j.jcf.2025.03.508","url":null,"abstract":"<div><h3>Objectives</h3><div>Heart rate reserve (HRR), the difference between resting heart rate (RHR) and peak heart rate (PHR), is commonly used to evaluate and prescribe exercise intensity in adults <span><span>(ACSM, 2021)</span><svg><path></path></svg></span>. HRR is less commonly used in children and young people (CYP), who are physiologically and metabolically different to adults. They have higher PHR and RHR during rest and exercise and both typically decline with age and fluctuate with changes in physical fitness. This study aimed to investigate the influence of age, fitness and illness on RHR, PHR and HRR in CYP with Cystic Fibrosis (CF).</div></div><div><h3>Methods</h3><div>Data from CYP with CF participating in <span><span>Project Fizzyo (UK)</span><svg><path></path></svg></span> were used. RHR was the average of <span><span>5 lowest HR values</span><svg><path></path></svg></span> from daily Fitbit monitoring. PHR came from a Polar H10 ECG chest strap worn during a 25-level 10-metre modified shuttle test (MST‐25). Fitness was defined by distance achieved in the MST‐25, <span><span>normalised for age</span><svg><path></path></svg></span>. Severity of illness was represented by FEV₁ % predicted. Linear regression was used to investigate associations between HRR and age, RHR, PHR, illness and fitness.</div></div><div><h3>Results</h3><div>134 participants (48.5% male, average age 10.1 years, average FEV₁ 90% predicted) performed the MST‐25 at baseline. Significant associations: Age and fitness explained 41% and 5% of the variability in RHR respectively, with RHR decreasing in older CYP. Fitness and illness explained 14% and 8% of the variability in PHR respectively. The HRR interval ranged between 110 bpm at age 6 to 123 bpm at age 16, increasing by 1.27 bpm (95% CI 0.13 - 2.4) per year, as children got older. PHR explained 46% of the variability in HRR, and PHR, age, fitness and illness combined explained 73% of the variability in HRR.</div></div><div><h3>Conclusion</h3><div>HRR is strongly associated with age in CYP with CF, and to a lesser degree fitness and illness. While proportional contribution of these factors to HHR may differ in adults, the HRR approach remains appropriate for evaluating and prescribing exercise intensity in CYP with CF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S7"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS15.02Impact of one versus two responsive CFTR variants on sweat chloride and FEV1 responses to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a real-world study","authors":"P.-R. Burgel ,&nbsp;J. Da Silva ,&nbsp;C. Martin ,&nbsp;E. Girodon ,&nbsp;J.-L. Paillasseur ,&nbsp;French CF National Reference network study group","doi":"10.1016/j.jcf.2025.03.577","DOIUrl":"10.1016/j.jcf.2025.03.577","url":null,"abstract":"<div><h3>Objectives</h3><div>It remains unknown whether responses to elexacaftor-tezacaftor-ivacaftor (ETI) vary according to the number of ETI-responsive <em>CFTR</em> variants in people with cystic fibrosis (pwCF).</div></div><div><h3>Methods</h3><div>Data from pwCF treated with ETI were obtained using the French adult ETI-real world study and the French Compassionate program. <em>CFTR</em> variants were classified according to their ETI-responsiveness, as determined in the French Compassionate Program. Sweat chloride concentrations with ETI and absolute change in sweat chloride and in ppFEV₁ following ETI initiation were described, comparing pwCF with one vs. two ETI-responsive variants.</div></div><div><h3>Results</h3><div>Among 1266 participants, 834 had two ETI-responsive variants and 432 had only one. Median [IQR] sweat chloride concentrations were lower in participants with two vs. one ETI-responsive variants; 36 [24; 50] mmol/l and 53 [26; 72] mmol/l, respectively (<em>P</em>&lt;0.0001). The proportion of participants with sweat chloride concentration &lt;30 mmol/l was 35.7% vs. 15.0% in those with two vs. one ETI-responsive variants, respectively (Chi-square, <em>P</em>&lt;0.00001). In multivariable analyses, the number of ETI-responsive variants was a determinant of sweat chloride concentration with ETI (<em>P</em>&lt;0.0001) but not of absolute change in ppFEV₁ following ETI initiation (<em>P</em>=0.80).</div></div><div><h3>Conclusion</h3><div>PwCF with two responsive <em>CFTR</em> variants have better correction of CFTR function than those with one responsive <em>CFTR</em> variant when treated with ETI, but sweat chloride response is not predictive of the change in ppFEV₁. These data suggest that maximal improvement in lung function is already obtained with current CFTR modulators and that no further lung function improvement may be expected from newer modulators with more potent restoration of CFTR function.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S30"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}