Journal of Cystic Fibrosis最新文献

{"title":"WS13.03The clinical characteristics of CFTR-related disorders (CFTR-RDs): retrospective study from a large national difficult CF diagnosis (DCFD) clinic","authors":"L. Weitnauer ,&nbsp;R. Robinson ,&nbsp;I. Felton ,&nbsp;D. Morris-Rosendahl ,&nbsp;E.W. Alton ,&nbsp;J.C. Davies ,&nbsp;N.J. Simmonds","doi":"10.1016/j.jcf.2025.03.566","DOIUrl":"10.1016/j.jcf.2025.03.566","url":null,"abstract":"<div><h3>Objectives</h3><div>The European Cystic Fibrosis Society recently published new guidelines on CFTR-RDs conditions caused by CFTR protein dysfunction but where cystic fibrosis (CF) diagnostic criteria are not met. At our Difficult CF Diagnosis (DCFD) clinic we systematically assess patients by genetic analysis and CFTR functional testing (sweat test (ST) ± nasal potential difference (NPD)) to reach a diagnosis. We also assess the phenotype for evidence of sinus, lung and pancreatic disease; as well as fertility status in males. Previously, CFTR-RDs were considered single-organ conditions. The new guidelines state that this is not essential for the diagnosis, particularly as clinical features can evolve over time. Here, we review the diagnostic and clinical characteristics of our cohort, with a focus on single versus multi-organ involvement.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed the health records of all patients diagnosed with CFTR-RD between 2017 and 2023 at our national DCFD clinic. We report their diagnostic and clinical characteristics.</div></div><div><h3>Results</h3><div>Of 166 patients referred, 44 (27%) received a diagnosis of CFTR-RD. All had ST, 42 (95%) required NPD. With extended analysis, 2 <em>CFTR</em> variants were identified in all but 2 (5%) (no patient had 2 CF-causing variants). The most common genotypes were F508del/R117H+7T (n=13, 30%) and F508del/5T (n=5, 11%). The most common clinical feature was infertility in men and lung disease in women (Table). 30 (68%) patients had ≥2 organs involved.</div></div><div><h3>Conclusion</h3><div>We describe key clinical features from our large cohort of people with CFTR-RD, with an expected male preponderance due to male fertility issues, but importantly a high frequency of additional organ involvement when systematic assessment is performed as per recent published guidelines.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S26"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205187","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":"WS16.03The prevalence and probability of cystic fibrosis-related diabetes in children under 10: a prospective cohort study","authors":"S. Kiss ,&nbsp;K. Ocskay ,&nbsp;P. Mátrai ,&nbsp;A. Párniczky","doi":"10.1016/j.jcf.2025.03.584","DOIUrl":"10.1016/j.jcf.2025.03.584","url":null,"abstract":"<div><h3>Objectives</h3><div>With the widespread adoption of cystic fibrosis transmembrane conductance modulator (CFTRm) therapies, the metabolic profile of people with cystic fibrosis is changing. We aimed to assess the prevalence and probability of the development of cystic fibrosis-related diabetes (CFRD) under the age of 10.</div></div><div><h3>Methods</h3><div>Data from the prospective CF-related Pancreatic Disorders Registry was analyzed using time-to-event analysis, the event being the diagnosis of CFRD. Kaplan-Meier curves illustrated the event as a function of age, for the total cohort and by sex as well. Log-rank tests compared males and females. Age at diagnosis was analyzed using histograms, calculating mean, median, and the percentage diagnosed under the age of 10. Eleven patients were excluded from time-to-event analyses who presented with CFRD at their first visit.</div></div><div><h3>Results</h3><div>Of the 135 children in the cohort (Table 1), 31 were diagnosed with CFRD, 11 at the beginning of follow-up and 20 during. Of all CFRD patients, 48.4% (n=15) were diagnosed before the age of 10 (Table 2), including 5 (16.1%) from those having CFRD at the beginning of follow-up. The analysis of patients without pre-existing CFRD indicated a 13.2% (95% CI: [5.1%; 20.5%]) probability of CFRD by the age of 10 years. No significant sex-based differences were observed in CFRD risk (p=0.353).</div></div><div><h3>Conclusion</h3><div>The observed distribution of CFRD diagnosis suggests a potential need for earlier screening in a subset of patients. Ongoing analyses incorporating modulator therapy as a covariate will provide a more complete understanding and inform optimal screening protocols.</div><div><strong>Funding:</strong> <em>National Research, Development and Innovation Fund (NRDI Fund) FK 138929; CF Trust Strategic Research Consortium Grant NU-000600</em></div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S32"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205188","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":"WS16.04The effects of cystic fibrosis transmembrane conductance regulator modulator therapy on glycaemic control in patients with cystic fibrosis: a meta-analysis","authors":"S. Kiss ,&nbsp;M.F. Juhász ,&nbsp;T. Kói ,&nbsp;K. Ocskay ,&nbsp;A. Párniczky","doi":"10.1016/j.jcf.2025.03.585","DOIUrl":"10.1016/j.jcf.2025.03.585","url":null,"abstract":"<div><h3>Introduction</h3><div>Cystic fibrosis-related diabetes (CFRD) significantly impacts health outcomes of people with cystic fibrosis (pwCF). Understanding the effects of cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapy on glycaemic control is crucial for improving overall health.</div></div><div><h3>Objective</h3><div>To evaluate the impact of CFTRm therapy on glycaemic control in pwCF.</div></div><div><h3>Methods</h3><div>A comprehensive literature search was conducted from January 1, 2011 to September 19, 2024, in PubMed, Embase, and Cochrane Central Register of Controlled Trials. Eligible studies included interventional trials comparing CFTRm therapy with either no treatment or placebo. Observational studies reporting data on glycemic outcomes in pwCF pre-therapy and on-therapy, as well as pwCF on-therapy compared to controls were eligible. Primary outcomes included oral glucose tolerance test (OGTT) results, internationally accepted continuous glucose monitoring (CGM) measures and haemoglobin A1c (HbA1c) levels. Two authors independently extracted data with full adherence to PRISMA guidelines. Data synthesis was performed by calculating mean differences (MD) with 95% confidence intervals (CI); data were pooled using a random-effects model. Regression analyses were performed to evaluate the relationship between the effects of CFTR modulator therapy and both patient age and length of therapy.</div></div><div><h3>Results</h3><div>Across 77 studies, CFTRm therapy significantly improved 120-minute glucose levels (MD, -0.74 mmol/L; 95% CI, -1.42 to -0.07), lowered HbA1c levels (MD, -0.31%; 95% CI, -0.55 to -0.07), and reduced time spent in hyperglycaemia (&gt;10 mmol/L) as measured by CGM (MD, -0.92%; 95% CI, -1.75 to -0.09). Regression analyses showed that earlier therapy initiation was associated with more stable glucose levels (p=0.0471) and better HbA1c values (p=0.0001).</div></div><div><h3>Conclusions</h3><div>CFTRm therapy significantly improved glycaemic control in pwCF. Earlier treatment initiation was associated with better outcomes.</div><div><strong>Funding:</strong> <em>National Research, Development and Innovation Fund (NRDI Fund) FK 138929; CF Trust Strategic Research Consortium Grant NU-000600</em></div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S32-S33"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205189","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":"WS16.06Amylase as a potential non-insulin adjunct to manage CF-related blood glucose levels","authors":"M. Putman ,&nbsp;M. Sathe ,&nbsp;R. Gallotto ,&nbsp;D. Borowitz ,&nbsp;S.D. Freedman","doi":"10.1016/j.jcf.2025.03.587","DOIUrl":"10.1016/j.jcf.2025.03.587","url":null,"abstract":"<div><h3>Background</h3><div>People with CF have a later peak in blood glucose after a meal than is seen in health; this delay is greater in those with impaired glucose tolerance. We hypothesized that an efficacious amylase could lead to improved post-prandial glucose patterns. ANG003 is a microbially-derived lipase, protease and amylase product. Its amylase is pH stable, can interact with substrate in the fed stomach and does not need enteric coating. A clinical study used continuous glucose monitoring (CGM) and C-peptide response to a test meal to investigate the impact of ANG003 on starch digestion and absorption.</div></div><div><h3>Methods</h3><div>This multicenter study evaluated the effect of a single dose of orally administered ANG003 in adults with CF. Subjects were randomized to either 40, 80 or 120 mg amylase given with microbial lipase and protease and a high-fat breakfast containing ∼100 gm total carbohydrates, including 20 gm of potato starch. A blinded Dexcom G6Pro CGM was placed 24 hours before each study and continued for 4 hours after the meal. Each subject was studied once without and once with the specified amylase dose. C-peptide levels were drawn prior to and 1, 2, 4 and 6 hours after each test meal.</div></div><div><h3>Results</h3><div>Fifty-one subjects were enrolled. Subjects without diabetes (n=32) had baseline glucose=110 mg/dL. Compared to no amylase, all doses shifted glucose curves to the left; a significant difference was seen with the 120 mg dose (p=0.04). No difference in C-peptide levels were observed compared to no enzyme. Fewer CGM readings below 70-80 mg/dL and fewer readings above 180-240 mg/dL were noted with ANG003 compared to no enzyme. No differences in glucose or C-peptide were noted in those subjects with diabetes (n=19); they had significant glycemic variability.</div></div><div><h3>Conclusion</h3><div>We saw an earlier and more physiologic shift of glucose absorption and fewer high and low glucose excursions not accompanied by increased insulin secretion. Amylase may play a supportive role in glucose homeostasis in CF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S33"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205191","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":"WS05.01Lipid nanoparticles and vesicles delivery tools to deliver mRNA and ribonucleoprotein to the lungs for the development of genome editing in cystic fibrosis","authors":"G. Maule ,&nbsp;S. Saxena ,&nbsp;A. Colliva ,&nbsp;S. Vodret ,&nbsp;J. Parot ,&nbsp;A. Molska ,&nbsp;E. Gurrieri ,&nbsp;M. Stancampiano ,&nbsp;S.E. Borgos ,&nbsp;D. Guidone ,&nbsp;A. Borrelli ,&nbsp;L.J.V. Galietta ,&nbsp;S. Hak ,&nbsp;S. Zacchigna ,&nbsp;A. Cereseto","doi":"10.1016/j.jcf.2025.03.516","DOIUrl":"10.1016/j.jcf.2025.03.516","url":null,"abstract":"<div><h3>Objectives</h3><div>Genome editing technologies hold great for the treatment of cystic fibrosis (CF). However, current delivery methods remain inefficient, posing a major barrier to their clinical translation.</div><div>The GenDel-CF project aims to develop in vivo delivery tools to transfer 1) mRNA and 2) ribonucleoprotein (RNP) expressing CRISPR-Cas9.</div></div><div><h3>Methods and Results</h3><div>For the first goal our consortium aims to develop novel lipid nanoparticle (LNP) formulations. We recently developed LNP-GD19 that were tested by encapsulating Cre-mRNA and delivered to reporter mice. LNPs were delivered via either intratracheal (IT) administration in adult mice or intravenous (IV) injection in neonates. We obtained high levels of Cre-mediated recombination resulting in mGFP expression throughout the lung parenchyma upon both administration routes. IT administration resulted nearly 80% of GFP-positive in secretory cells, 48% in epithelial cells from the airways and submucosal glands, and 75% in bronchial epithelial and alveolar type 1 cells. This pointed to IT delivery as the best delivery route for targeting epithelial cells critical for CF therapy.</div><div>For the second aim, consisting in CRISPR-Cas delivery as RNP we focused on engineered vesicles as promising delivery systems for genome editing. We exploited base editors as editing systems, specifically ABE8e-SpCas9, due to their proven efficiency in precisely and effectively repairing CFTR mutations. The GE-vesicles were produced using membrane anchoring motifs to capture maximal amounts of ABE8e-SpCas9 and sgRNA. Particles were characterized for size, particle number and editor content showing overall homogenous size in the range of 100-130 nm and efficient encapsulation of the ABE8e-SpCas9 resulting in up to 60% of base conversion.</div></div><div><h3>Conclusions</h3><div>In conclusion, our GD19 LNP formulation GE-vesicles lay the foundation for editing tools delivery to repair CF mutations.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S9-S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205222","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":"WS07.05Indirect evaluation of lung condition by means of low field nuclear magnetic resonance following chest physiotherapy or modulator drug administration in cystic fibrosis patients","authors":"M. Abrami ,&nbsp;A. Biasin ,&nbsp;M. Maschio ,&nbsp;M. Conese ,&nbsp;M. Confalonieri ,&nbsp;F. Gerin ,&nbsp;F. Salton ,&nbsp;P. Confalonieri ,&nbsp;B. Ruaro ,&nbsp;G. Grassi ,&nbsp;M. Grassi","doi":"10.1016/j.jcf.2025.03.532","DOIUrl":"10.1016/j.jcf.2025.03.532","url":null,"abstract":"<div><h3>Objectives</h3><div>as most cystic fibrosis (CF) patients progress to respiratory failure, lung functionality assessment is pivotal. We previously developed a test that monitors airways condition measuring the spin-spin relaxation time (T_2m) of the water hydrogens present in sputum by Low Field-Nuclear Magnetic Resonance (LF-NMR). This study further investigates the significance of T_2m by exploring: 1) influence on T_2m of sputum contamination by saliva, 2) T_2m relation with sputum mesh size, 3) correlation with the effects of chest physiotherapy (CP) and of the cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI).</div></div><div><h3>Methods</h3><div>T_2m was measured in the sputum of 16 CF patients before/after CP and in 9/16 patients before/after ETI administration. FEV₁/C reactive protein (CRP)/erythrocyte-sedimentation rate (ESR) and sweat chloride concentration were measured by standard techniques. Sputum contamination by saliva/sputum mesh size were determined mathematically.</div></div><div><h3>Results</h3><div>We present a novel mathematical approach to correct T_2m values in sputum samples contaminated by saliva and to determine T_2m relation to sputum mesh size. Additionally, we prove that T_2m detects the lack of significant effects on lung function by CP (confirmed by FEV₁). Moreover, T_2m detects the ETI positive effects on lung function (evaluated by FEV₁) and inversely correlates with the CRP/ESR/chloride sweat concentration.</div></div><div><h3>Conclusion</h3><div>These data strengthen the rationale for T_2m employment in CF lung disease monitoring.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S15"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205329","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":"WS14.06Novel targets to regulate the abundance of G542X CFTR mRNA","authors":"A.F. Henriques,&nbsp;A. Abrantes,&nbsp;C.M. Farinha","doi":"10.1016/j.jcf.2025.03.575","DOIUrl":"10.1016/j.jcf.2025.03.575","url":null,"abstract":"<div><h3>Background and Objectives</h3><div>The <em>CFTR</em> gene contains over 2,100 documented variants classified into 7 classes based on their impact on CFTR protein. Despite the advances with the modulators, 10-15% of patients, including those with nonsense variants (Class I), lack targeted therapies. Nonsense variants, such as the prevalent G542X, introduce premature stop codons (PTCs), triggering nonsense-mediated decay (NMD) and degrading CFTR mRNA. Personalized therapies for these variants remain an unmet need.</div></div><div><h3>Methods and Results</h3><div>As we did before for common variants (1), we focused on transcriptomic and proteomic profiles of 16HBE14o- cells bearing G542X-CFTR. Differential expression analysis revealed 201 transcripts, and 35 proteins uniquely altered in G542X cells. Enrichment analysis highlighted processes like “regulation of transcription,” “RNA metabolic process,” and “RNA-binding,” suggesting key roles in CFTR mRNA stability.</div><div>Validation identified 7 upregulated and 4 downregulated genes. Additionally, we found that the knockdown of the RNA binding proteins TUT1 (Terminal Uridylyl Transferase 1) and HNRNPUL2 (Heterogeneous Nuclear Ribonucleoprotein U Like 2) has a considerable effect in the levels of CFTR mRNA in G542X cells. A similar effect was found under overexpression of ZNF793 (Zinc Finger Protein 793) in the same G542X cell line. Ongoing work aims to assess protein expression and explore combinatory strategies for synergistic therapeutic outcomes.</div></div><div><h3>Conclusion</h3><div>We identified novel RNA-binding proteins as regulators of CFTR mRNA abundance in G542X cells, paving the way for targeted therapies combining NMD inhibition and PTC readthrough to restore CFTR expression in patients lacking current treatment options.</div><div>Acknowledgements: Work supported by Emily's Entourage and center grants to BioISI UIDB/04046/2020 and UIDP/04046/2020 (<span><span>https://doi. org/10.54499/UIDB/04046/2020</span><svg><path></path></svg></span>) from FCT, Portugal (to BioISI).</div><div>[1] <span><span>www.cftr2.org</span><svg><path></path></svg></span></div><div>[2] Santos L et al (2023). Cell Biosci 13, 26</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S29"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205338","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":"WS15.03Elevated sweat chloride concentrations in people with cystic fibrosis with at least one N1303K, 2789+5G>A or R334W treated with elexacaftor/tezacaftor/ivacaftor","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.2025.03.578","DOIUrl":"10.1016/j.jcf.2025.03.578","url":null,"abstract":"<div><h3>Objectives</h3><div>Data from the French Compassionate Program have shown that people with CF (pwCF) and no F508del variant but at least one N1303K, 2789+5G&gt;A or R334W treated with elexacaftor-tezacaftor-ivacaftor showed clinical improvement with no or small decrease in sweat chloride concentration. We sought to characterize the sweat chloride concentration with ETI in people with CF with these variants, according to the second <em>CFTR</em> variant.</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 were described according the second CFTR variant.</div></div><div><h3>Results</h3><div>Among 163 participants with at least one N1303K, 2789+5G&gt;A or R334W variants, 55 had an F508del, 19 had a non-F508del responsive variant, 20 had two N1303K, 2789+5G&gt;A or R334W variants and in 69 participant the other variant was non-responsive to ETI. In these subgroups, median [IQR] sweat chloride concentrations were 48 [37; 65] mmol/l, 28 [22; 50] mmol/l, 88 [79; 95] mmol/l, and 90 [84;100] mmol/l, respectively (<em>P</em>&lt;0.0001). All participants with two N1303K, 2789+5G&gt;A or R334W variants or with one of these variants and a non-ETI responsive variant had sweat chloride concentrations with ETI ≥60 mmol/l; in those with at least one F508del or another non-F508del responsive variant, only 42.6% had sweat chloride concentrations ≥60 mmol/l.</div></div><div><h3>Conclusion</h3><div>These data confirm that sweat chloride concentrations are often elevated in people with CF with N1303K, 2789+5G&gt;A or R334W variants treated with ETI. Only those with another ETI-responsive variant may show sweat chloride concentration &lt;60 mmol/l.</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":"144205351","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":"WS15.04Elexacaftor/tezacaftor/ivacaftor CFTR modulators mitigates senescence in cystic fibrosis","authors":"V. Bezzerri ,&nbsp;A.M. Hristodor ,&nbsp;T. Gunawardena ,&nbsp;M. Borgatti ,&nbsp;A. Vella ,&nbsp;C. Boni ,&nbsp;D. Olioso ,&nbsp;F. Quiri ,&nbsp;G. Lippi ,&nbsp;T. Moraes ,&nbsp;M. Cipolli","doi":"10.1016/j.jcf.2025.03.579","DOIUrl":"10.1016/j.jcf.2025.03.579","url":null,"abstract":"<div><h3>Objectives</h3><div>Impaired CFTR function causes loss of chloride and bicarbonate efflux across epithelia, leading to dehydration of the airway surface liquid and increased oxidative stress.</div><div>Senescence is a cellular program characterized by irreversible cell cycle arrest largely triggered by oxidative stress. While in the short-term senescence serves as a protective mechanism to prevent damaged cells from proliferating and supporting wound healing, in the long term it may sustain the “inflammaging” process, increasing the risk of age-related disorders.</div><div>Thus, we sought to assess the role of senescence in Cystic Fibrosis (CF) pathophysiology and the effect of elexacaftor/tezacaftor/ivacaftor (ETI) treatment on this cellular program.</div></div><div><h3>Methods</h3><div>CF (F508del) and healthy control airway epithelia (hBEC/hNEC) with similar ages and culture passages, were compared.</div></div><div><h3>Results</h3><div>The p53 pathway was upregulated in CF along all the cell models tested. This was recapitulated by inhibiting CFTR-dependent chloride efflux with CFTR(inh)-172 in healthy hBECs, suggesting a direct role of CFTR function on the onset of senescence. The senescence-associated secretory phenotype (SASP) was found in CF-hBEC. CF airway epithelial cells were enlarged and flattened compared to healthy controls, showing an increased expression of cytoskeletal component vimentin and decreased lamin B1. CFTRinh-172 induced vimentin expression in healthy airway epithelial cells, whereas ETI treatment reduced both vimentin and lamin B1 levels in CF cells. Eventually, clinical data revealed that ETI therapy is able to reduce plasmatic levels of SASP-related soluble mediators in patients with CF.</div></div><div><h3>Conclusion</h3><div>Taken together, these results indicate that CF airway epithelia are generally senescent. Cellular senescence could be a major driver of the constitutive inflammation reported in CF lungs. ETI is able to mitigate senescence both in vitro and in vivo, highlighting potential benefits that may go far beyond the expected effects.</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":"144205352","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":"WS10.05Downregulation of inflammatory cytokines and miRNAs by novel inhalable formulations bearing Iloprost in primary human cystic fibrosis nasal epithelial cells","authors":"A. Carbone ,&nbsp;P. Soccio ,&nbsp;E.F. Craparo ,&nbsp;P. Vitullo ,&nbsp;S. Bonsignore ,&nbsp;P. Tondo ,&nbsp;C. Scialabba ,&nbsp;G. D'Abrosca ,&nbsp;S. Di Gioia ,&nbsp;D. Lacedonia ,&nbsp;G. Cavallaro ,&nbsp;M. Conese","doi":"10.1016/j.jcf.2025.03.550","DOIUrl":"10.1016/j.jcf.2025.03.550","url":null,"abstract":"<div><h3>Objectives</h3><div>Cystic fibrosis (CF) lung disease hallmarks are mucus obstruction, opportunistic bacterial infections (e.g. by <em>Pseudomonas aeruginosa</em>), and an unresolvable inflammatory response. CF hyper-inflammation remains an orphan drug condition. Our aim is to develop suitable culture models from human beings in order to optimize inhalable smart drug-delivery systems, composed by Nano-into-mycro (NiM) formulations, in models mimicking in vivo airway epithelia and so to translate results into patients with CF to dampen lung inflammation. We have identified nasal epithelial cells (NEC), grown at Air Liquid Interface (ALI) culture conditions, as a suitable model obtained from nasal brushings in CF patients.</div></div><div><h3>Methods</h3><div>To date, nasal epithelial brushings from 8 CF individuals (homozygous or compound heterozygous for the F508del mutation) were collected and isolated cells were expanded under conditional reprogramming culture (CRC) method. ALI cultures, producing endogenous mucus, were challenged with <em>P. aeruginosa</em> lipopolysaccharide (LPS) in the absence or presence of mucopenetrating NiM formulations (pegylated or not) containing Iloprost (Ilo), a prostacyclin analogue. The expression of cytokines (TNF-<em>α</em>, IL-6, IL-1<em>ß</em>, IL-8) and miRNAs (miR-145, -146a, -17), all involved in inflammation, were analyzed by real-time PCR.</div></div><div><h3>Results</h3><div>A downregulation for all cytokines by either free Ilo and both NiM formulations as compared with LPS only was observed. miR-145, -146a, -17 levels were significantly reduced by NiM-PEG-Ilo as compared with LPS only.</div></div><div><h3>Conclusion</h3><div>The CF hyper-inflammation state might be modulated by novel inhalable NiM formulations containing Iloprost in an advanced human respiratory epithelial cell model, an ex-vivo pre-clinical model for precision medicine in CF.</div><div>Funded by European Union-NextGenerationEU Project PE_00000019: “Health Extended ALliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine-HEAL ITALIA”.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S21"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205584","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}