Journal of Cystic Fibrosis最新文献

{"title":"Title Page","authors":"","doi":"10.1016/S1569-1993(25)01477-8","DOIUrl":"10.1016/S1569-1993(25)01477-8","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page ii"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204920","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":"WS02.01Provider perspectives related to the care of sexual and gender minority people living with cystic fibrosis in the United States and Canada","authors":"T. Kazmerski ,&nbsp;O. Stransky ,&nbsp;M. Lee ,&nbsp;A. Alpern ,&nbsp;J. Greenberg ,&nbsp;R. Jain ,&nbsp;M. Lunn ,&nbsp;J. Palla ,&nbsp;K. Prangley ,&nbsp;R. Salyer ,&nbsp;V. Tangpricha ,&nbsp;K. Kidd ,&nbsp;G. Sawicki ,&nbsp;PRIDE-CF Community Partner Group","doi":"10.1016/j.jcf.2025.03.498","DOIUrl":"10.1016/j.jcf.2025.03.498","url":null,"abstract":"<div><h3>Objectives</h3><div>LGBTQIA+ people face significant health inequities. We examined CF providers’ attitudes and practices toward the care of LGBTQIA+ people with CF via the PRIDE-CF Study.</div></div><div><h3>Methods</h3><div>We designed and administered a survey to United States (US) and Canadian (CA) CF providers in 2024. We compared response distributions with Chi-square tests.</div></div><div><h3>Results</h3><div>A total of 389 providers (330 US, 59 CA) completed the survey. Of all participants, 6% reported discomfort working with LGBTQIA+ people, and 15% felt that there are only two genders. Most (87%) agreed that asking about sexual orientation and gender identity is important to healthcare, and 63% agreed that gender-affirming hormone therapy is safe in CF. Most (86%) felt training on supporting LGBTQIA+ people would help them be better clinicians. US providers reported greater comfort in talking to patients about sexual orientation (US 73% <em>vs.</em> CA 53%, p&lt;0.01) and gender identity (US 74% <em>vs.</em> CA 54%, p&lt;0.01) as well as referring for gender-affirming mental health (US 83% <em>vs.</em> CA 56%, p&lt;0.01), medical (US 67% <em>vs.</em> CA 43%, p&lt;0.01), and surgical care (US 46% <em>vs.</em> CA 28%, p=0.02). US and CA providers had different beliefs on who has the primary role in LGBTQIA+ care for people with CF (US 51% CF team, 39% primary care <em>vs.</em> CA 25% CF team, 65% primary care, p&lt;0.01). US providers were more likely to ask CF patients about their sexual orientation (US 54% <em>vs.</em> CA 33%, p&lt;0.01), gender identity (59% US <em>vs.</em> 43% CA, p=0.04), and affirmed name and pronouns (75% US <em>vs.</em> 63% CA, p=0.07). US providers were more likely to have been trained to support LGBTQIA+ people (US 43% <em>vs.</em> CA 20%, p&lt;0.01).</div></div><div><h3>Conclusion</h3><div>CF providers valued addressing LGBTQIA+ health concerns but lacked expertise and resources to routinely provide this care. CA providers reported less comfort and practice differences compared to US providers. Future PRIDE-CF work will explore health experiences and outcomes of LGBTQIA+ people with CF.</div><div><strong>Funding:</strong> <em>CF Foundation(KAZMER23A0-HETS)</em></div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S3"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204925","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":"WS05.05SPL5AC, MUC5AC Lowering ASO for cystic fibrosis and other muco-obstructive diseases","authors":"E. Ozeri-Galai ,&nbsp;Y.S. Oren ,&nbsp;C.D. Stampfer ,&nbsp;R.M. Elgrabli ,&nbsp;T. Blinder ,&nbsp;T. Mordechai ,&nbsp;S.A. Jubeh ,&nbsp;B. Kerem ,&nbsp;G. Hart","doi":"10.1016/j.jcf.2025.03.520","DOIUrl":"10.1016/j.jcf.2025.03.520","url":null,"abstract":"<div><h3>Background</h3><div>Airway mucus functions as the first line of defense against pathogens and toxins. The major components of the airway mucus are the mucins, MUC5AC and MUC5B. In CF, defective CFTR channel activity leads to dehydrated mucus and increased mucin content. In muco-obstructive diseases, such as CF, asthma, COPD, and NCFB, mucins are overexpressed due to goblet cell hyperplasia and the ratio of MUC5AC to MUC5B is elevated, causing thick mucus, airway obstruction, and chronic infections and inflammation. Splisense is developing an antisense oligonucleotide (ASO) drug aiming to reduce MUC5AC levels in patients with CF and other muco-obstructive diseases (Asthma, COPD and NCFB), facilitating efficient mucus clearance and alleviating respiratory blockage and inflammation.</div></div><div><h3>Methods</h3><div>Splisense ASOs designed and optimized using a proprietary algorithm were screened and the effect of highly potent lead candidate ASOs was further analyzed in IL-13 induced primary HBEs using RT-qPCR and Western Blot. The lead candidate was further analyzed in industry standard disease mouse models.</div></div><div><h3>Results</h3><div>The SPL5AC clinical candidate ASO was found to be highly potent and effectively delivered through the mucus layer to IL-13-induced HBEs, leading to a significant reduction in MUC5AC RNA and protein levels. In vivo studies in muco-obstructive disease mouse models demonstrated that SPL5AC reduced Muc5ac levels, resulting in improved clinical features typical of muco-obstructive diseases. These included a reduction in mucus plugs, goblet cell hyperplasia, and an attenuated immune response. Initial tox studies indicate the promising safety profile of SPL5AC.</div></div><div><h3>Conclusions</h3><div>Restoring proper mucus viscoelasticity and clearance in the lungs of patients with muco-obstructive diseases like CF, remains a major goal. Our results demonstrate that SPL5AC ASO has a potential therapeutic benefit for CF and other muco-obstructive patients with the objective to advance to first in Human in 2025.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S10-S11"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204930","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":"WS05.06Design of an adenine base editor for temporospatial control of editing","authors":"I. Zollo ,&nbsp;L. Santos ,&nbsp;J. Alves ,&nbsp;A.S. Coroadinha ,&nbsp;P.T. Harrison ,&nbsp;C.M. Farinha","doi":"10.1016/j.jcf.2025.03.521","DOIUrl":"10.1016/j.jcf.2025.03.521","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Despite advances with modulators, 10-15% of people with cystic fibrosis, particularly those with nonsense variants, still lack effective treatments. For these cases, gene-based therapies offer the most promising path to a cure. Among gene editing tools, Adenine Base Editor (ABE) is particularly suitable for correcting W1282X, the second most common CF-causing variant without a therapy. However, it remains unclear which cell types in the lung epithelium, and how many of them, need editing to restore CFTR function to therapeutic levels.</div></div><div><h3>Methods and Results</h3><div>We developed a basal cell line bearing W1282X (BCi W1282X-CFTR) able of differentiating into airway epithelial cell types (1). Additionally, we engineered a split version of ABE (SplitABE) that allows temporal control of editing. Preliminary data show SplitABE reverts the premature stop codon to WT while minimizing bystander edits.</div><div>Here, we present a strategy integrating temporal and spatial control of ABE by placing the SplitABE cassette under five cell-type-specific promoters, targeting basal, ciliated, secretory (type 1 and 2), and ionocyte cells (2). These plasmids were used to transfect 293T cells for large-scale lentiviral particle production. Infectious titers, determined via ddPCR after transducing BCi W1282X-CFTR cells, ranged between 7E+06 and 1.5E+07 IU/mL. These titers are now being used to transduce BCi W1282X-CFTR cells at varying MOIs to establish cell lines with cell-type-specific SplitABE expression.</div></div><div><h3>Conclusion</h3><div>This advanced gene-editing platform, combined with a robust cellular model, will help pinpoint critical cellular targets for CFTR correction and optimize strategies for potential clinical application.</div><div>1. Santos L et al (2023) J Cyst Fibr 22 (S2), S32.</div><div>2. Zollo I et al (2024) J Cyst Fibr 23 (S2), S162.</div><div><strong>Acknowledgements:</strong> Work supported by grants HARRIS21G0 and FARINH24G0 from CFF and centre grants UIDP/04046/2020 and UIDB/04046/2020 from FCT, Portugal (to BioISI).</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S11"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204931","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":"WS06.01Prenatal CFTR Modulator Exposure: a Review of the European and U.S. Experience","authors":"S. Szentpetery ,&nbsp;J. Taylor-Cousar ,&nbsp;C. Luna Parades ,&nbsp;I. Sermet-Gaudelus ,&nbsp;P. Aleksander ,&nbsp;A. Kowalik ,&nbsp;A. Morales-Tirado ,&nbsp;S. Gartner-Tizzano ,&nbsp;C. de Manuel-Gómez ,&nbsp;B. Fabrizzi","doi":"10.1016/j.jcf.2025.03.522","DOIUrl":"10.1016/j.jcf.2025.03.522","url":null,"abstract":"<div><h3>Objectives</h3><div>Evaluate clinical outcomes, ethical considerations, and emerging data from U.S. and European cases of prenatal elexacaftor-tezacaftor-ivacaftor (ETI) exposure in cystic fibrosis (CF) pregnancies, focusing on treatment timing, postnatal management, and access disparities.</div></div><div><h3>Methods</h3><div>Case data were gathered via standardized tools, including REDCap, from published and ongoing reports. Clinical outcomes, prenatal, postnatal findings, and complications were analyzed.</div></div><div><h3>Results</h3><div>In U.S. cases, 78% of CF infants were diagnosed via amniocentesis (mean 18 6/7 weeks). Abnormal prenatal ultrasounds occurred in 89% of cases - echogenic or dilated bowel loops. These resolved in all cases after a mean ETI treatment of 5 5/7 weeks. Postnatal complications included NICU admission (55%), transient feeding or meconium passage issues. Sweat chloride averaged 69 mmol/L, and 71% of breastmilk-fed infants were found to be pancreatic sufficient.</div><div>In European cases, 83% were diagnosed via amniocentesis and 82% had abnormal ultrasounds. Resolution of findings occurred in 63% after a mean ETI treatment duration of 6 2/7 weeks. Postnatal complications included unresolved meconium ileus in three infants, requiring enemas or bowel resection. Sweat chloride averaged 83 mmol/L, and pancreatic sufficiency was transient, in contrast to the reported U.S. cases. Fourteen French dyads who received prenatal treatment will also be reviewed.</div><div>Adverse maternal events were rare, with occasional rash or mild transaminase elevation. Neonatal complications included one case of hyperbilirubinemia. Long-term follow-up showed improved pancreatic function in infants transitioning to oral CFTR modulators.</div></div><div><h3>Conclusion</h3><div>Prenatal ETI exposure shows promise in improving outcomes for CF infants, resolving prenatal abnormalities, and supporting early pancreatic function. Standardized protocols, equitable access, and further study are needed to address unresolved cases and ensure long-term safety.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S11"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204932","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":"WS04.06Observations on CFTR modulators and pancreatic function in a clinical trial of ANG003, a novel pancreatic enzyme replacement therapy in people with cystic fibrosis","authors":"S.D. Freedman ,&nbsp;M. Sathe ,&nbsp;M. Clarkin ,&nbsp;D. Gallotto ,&nbsp;D. Borowitz","doi":"10.1016/j.jcf.2025.03.515","DOIUrl":"10.1016/j.jcf.2025.03.515","url":null,"abstract":"<div><h3>Background</h3><div>Highly efficacious CFTR modulators have greatly improved the daily lives of people with CF. Some patients and providers have attributed improvements in gastrointestinal symptoms to improved pancreatic function. A clinical study in people with cystic fibrosis of ANG003, a novel, microbially-derived lipase, protease and amylase product, required proof of exocrine pancreatic insufficiency as an inclusion criterion but did not have exclusions for concomitant CFTR modulators. We report observations about pancreatic functional status at baseline in this cohort.</div></div><div><h3>Methods</h3><div>This multicenter, randomized, parallel, active-treatment study evaluated the safety, tolerability and effect of a single dose of orally administered ANG003 in adult subjects with CF and documented EPI based on fecal elastase (NCT06052293).</div></div><div><h3>Results</h3><div>We enrolled 51 subjects (53% male; 94% white). Mean age was 30 years (range=18-58). On study entry, subjects were taking ∼5 capsules of porcine pancreatic enzyme replacement therapy per meal and 3 per snack (mean=20 capsules/day (range: 6-43 capsules); mean lipase units per day 548,000 (168,000-1,080,000); mean 8,000 lipase units/kg/day; 22% of subjects were taking &gt;10,000 units/kg/day). CFTR modulators were being taken by 47 subjects (92%). All were taking elexacaftor/ tezacaftor/ivacaftor with the exception of two subjects taking ivacaftor alone. Subjects had been taking these modulators for a median of 3.7 years (range 1 month-6.6 years). Fecal elastase values were all in the range consistent with severe pancreatic insufficiency. The median value was &lt;40 ug/g.</div></div><div><h3>Conclusion</h3><div>These data add to the body of information that adults taking highly efficacious CFTR modulators are not associated with objective improvement in pancreatic function. In addition, we observed lack of conformity with guidelines on limits of pancreatic enzyme dose per day.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S9"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205221","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":"WS03.02High-intensity interval training and moderate-intensity continuous training are equivalent in improving exercise capacity at submaximal intensity in adults with cystic fibrosis","authors":"W. Gruber ,&nbsp;J. Koop ,&nbsp;F.A. Haegele ,&nbsp;C. Falkenberg ,&nbsp;S. Dewey ,&nbsp;B. Weiser ,&nbsp;A. Bosy-Westphal","doi":"10.1016/j.jcf.2025.03.505","DOIUrl":"10.1016/j.jcf.2025.03.505","url":null,"abstract":"<div><h3>Objectives</h3><div>This randomised controlled trial investigates the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on exercise capacity at submaximal exercise intensity in adult people with Cystic Fibrosis (pwCF).</div></div><div><h3>Methods</h3><div>60 adult pwCF (34f/26m, mean age 38.9±10.4yrs, 19-58years, ppFEV₁ 67.9±19.3, 35.0-110.0%) agreed to participate. Cycle-ergometry was used to determine Oxygen Uptake (VO2) and Workload (W) at Ventilatory Threshold 2 (VT2). Participants were randomly assigned to either the HIIT or MICT group, with matching based on lung disease severity (ppFEV1 35-70% or &gt;70%). Both groups exercised 5 times per week, including three cycle ergometer sessions. The HIIT group performed 10 bouts of 1 minute at 90% VO2peak, followed by 2 minutes of active recovery at 40% VO2peak for a total of 30 minutes per session (10 minutes high-intensity, 20 minutes active recovery), while the MICT group completed 30 minutes at a constant load of 60% VO2peak. Data were collected during a 4-week inpatient rehabilitation program at two specialized CF institutions.</div></div><div><h3>Results</h3><div>VO2_VT2 and W_VT2 increased significantly (p&lt;0.001) in both groups (HIIT: VO2peak, D +9.4%, Wpeak +10.3%, MICT: VO2peak, D +14.0%, Wpeak +15.1%). The MICT group had slightly greater changes, but the time x training interaction revealed non-significant results (p&gt;0.05). No adverse events were reported, and the dropout rate was similar between groups</div></div><div><h3>Conclusion</h3><div>HIIT and MICT were equally effective in improving exercise capacity in adult pwCF during this 4-week rehabilitation course. The choice of training modalitiy should be individualized, considering aspects such as available time, initial exercise capacity, individual interests, preferences, and enjoyment. As this study represents a short-term exercise intervention, future studies should investigate the comparative effectiveness of these training modalities over longer time periods.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S6"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205322","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":"WS03.06A novel use of electrical impedance tomography in children with cystic fibrosis","authors":"J. Depiazzi ,&nbsp;C. Bourke ,&nbsp;A. Withers","doi":"10.1016/j.jcf.2025.03.509","DOIUrl":"10.1016/j.jcf.2025.03.509","url":null,"abstract":"<div><h3>Objectives</h3><div>Around 40% of children with cystic fibrosis (CF) have tracheobronchomalacia (TBM), an increased airway collapsibility. TBM is associated with increased respiratory symptoms and hospitalisations requiring regular airway clearance (AWC). Electrical impedance tomography (EIT) is a novel technology that may assist the titration of positive expiratory pressure (PEP) to optimise AWC through ventilation visualisation. Our aim is to establish if EIT is a feasible, useful clinical outcome measure in non-sedated typically developing children with CF and TBM to titrate PEP therapy for AWC.</div></div><div><h3>Methods</h3><div>Ten children aged between one and fifteen years with CF and a previous TBM diagnosis were invited to participate in a feasibility study. Whilst monitored by EIT, participants performed two-minutes of PEP breathing at 5, 10, 15 and 20 cmH₂O, each followed by one minute breathing at no resistance. Outcome measures were determined for tolerability of the monitoring; ease of administration; interpretation by the clinician; and clinical feasibility. A score of 70% or above was deemed successful for each criterion to determine the overall feasibility of EIT in titrating PEP therapy for AWC.</div></div><div><h3>Results</h3><div>All criteria met success in domains of tolerability (mean 98%; range 86-100) and intervention completion (mean 95%; range 90-100). The EIT regions of interest display (mean 96%; range 80-100) and software data analysis (mean 96%; range 90-100) allowed differences in regional lung ventilation to be observed with different PEP resistances. Ease of clinical use criteria highlighted difficulties with automated software functionality and impact on clinician time (mean 66%; range 10-100 and 75%; 0-100 respectively). In 50% of children, recommendations for airway clearance routine changes were made.</div></div><div><h3>Conclusion</h3><div>In children with CF and TBM, EIT maybe a feasible tool for examining, titrating and optimising PEP for airway clearance.</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":"144205326","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":"WS07.04Baseline variability in percent predicted forced expiratory volume in one second predicts short-term lung function response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis","authors":"H. Bhandol ,&nbsp;B. Quon","doi":"10.1016/j.jcf.2025.03.531","DOIUrl":"10.1016/j.jcf.2025.03.531","url":null,"abstract":"<div><h3>Objectives</h3><div>Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a highly effective drug, improving Percent Predicted Forced Expiratory Volume in One Second (PPFEV₁) in People With Cystic Fibrosis (PWCF). Lung function response to ETI varies but limited research exists on predictors of PPFEV₁ response. This study examined how pre-ETI PPFEV₁ variability influences short-term (≤12 months) PPFEV₁ response to ETI. We hypothesised that greater pre-ETI PPFEV₁ variability predicts larger PPFEV₁ changes, reflecting reversible airflow obstruction from airway inflammation and mucus plugging.</div></div><div><h3>Methods</h3><div>Observational study with 1,619 PWCF starting ETI, followed in the CF Canada Registry. Eligibility criteria: ≥4 PPFEV₁ measurements within 2 years before ETI initiation (baseline period) and ≥1 PPFEV₁ value within 12 months post-ETI. Wilcoxon matched-pairs sign-rank test was used to evaluate ETI's effect on PPFEV₁. Pre-ETI variability was assessed via median deviation from the highest PPFEV₁ in the baseline period, consistent with previously described methodologies. Correlation between pre-ETI variability and maximum PPFEV₁ change from baseline to 1 year post-ETI was analysed using Spearman's correlation (ρ).</div></div><div><h3>Results</h3><div>The median for the maximum post-ETI PPFEV₁ change from baseline was 11.6 (IQR:5.4 – 19.2; p&lt;0.001). Median baseline age was 26.6 years and PPFEV₁ 67.6%. Pre-ETI PPFEV₁ variability correlated with maximum post-ETI PPFEV₁ change but was weak (ρ=0.11; p&lt;0.001). Correlation strength varied by lung disease severity: PPFEV₁&lt;40% (n=281, ρ=0.35; p&lt;0.001), 40%≤PPFEV₁&lt;70% (n=572, ρ=0.14; p&lt;0.001), 70%≤PPFEV₁&lt;90% (n=423, ρ=0.14; p=0.005), and PPFEV₁≥90% (n=343, ρ=0.02; p=0.66).</div></div><div><h3>Conclusion</h3><div>Increased pre-ETI PPFEV₁ variability correlated with greater 1 year PPFEV₁ response post-ETI, with stronger correlations at lower baseline PPFEV₁. This suggests variable airflow obstruction predicts short-term lung function response to ETI, particularly in PWCF with lower baseline lung function.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S14-S15"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205328","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":"WS14.04Small molecules acting as eRF degraders differently rescue G542X and W1282X-CFTR function","authors":"A. Borrelli ,&nbsp;A. Venturini ,&nbsp;M. De Santis ,&nbsp;F. Ciciriello ,&nbsp;L. Galietta","doi":"10.1016/j.jcf.2025.03.573","DOIUrl":"10.1016/j.jcf.2025.03.573","url":null,"abstract":"<div><h3>Objectives</h3><div>Nonsense mutations produce severely truncated forms of the CFTR chloride channel that are insensitive to presently available CFTR modulators. Pharmacological read-through (RT) of the ribosome stalled at the PTC site allow continuation of the protein synthesis. RT is limited by the nonsense mediated mRNA decay (NMD), that degrades mutant mRNA. We reported that G542X-CFTR is the most sensitive mutation to RT and the W1282X is the most responding to NMD inhibition. eRF degraders have been reported as effective on PTCs. We evaluated CC-90009 and SRI41315, an eRF3a and eRF1 degrader, on G542X-CFTR and W1282X-CFTR.</div></div><div><h3>Methods</h3><div>16HBE14o- cells with the G542X-CFTR mutation were treated for 24 h with different drug combinations containing CC-90009 (0.1 µM) or SRI-41315 (15 µM) with/without VX-809 (1 µM), and ELX-02 (200 µM), as a RT agent, or SMG1i (1 µM), as a NMD inhibitor. We evaluated the rescue of CFTR function using Isc recordings. CFTR rescue was also evaluated with the halide-sensitive yellow protein (HS-YFP) assay on 16HBE14o- cells expressing W1282X-CFTR.</div></div><div><h3>Results</h3><div>In 16HBE14o- cells we found little effect of CC-90009 in rescuing W1282X-CFTR. CC-90009 was effective on G542X-CFTR in combination with a RT agent. We found a significant effect of SRI-41315 on W1282X-CFTR in HS-YFP assay when combined with SMG1i. No significant effect was observed by Isc experiments when we treated G542X-CFTR cells with SRI-41315, either with RT agents or NMD inhibitor.</div></div><div><h3>Conclusions</h3><div>The eRF3a degrader CC-90009 has a role in potentiating RT, since it is effective on G542X-CFTR in combination with ELX-02, while the eRF1 degrader SRI-41315 is particularly active on W1282X-CFTR together with SMG1i. These results suggest that eRF degraders have different involvement in RT and NMD mechanisms.</div><div><strong>This work was supported by:</strong> the Cystic Fibrosis Foundation (GALIET22I0), the Italian Cystic Fibrosis Foundation (FFC#9/2022 and GMRF#1/2024), and the Italian Ministry of Health (GR-2018-12367126).</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S28-S29"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205336","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}