Drugs R D. 2025 Jun 23. doi: 10.1007/s40268-025-00514-9. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Lumacaftor is an active ingredient in the US Food and Drug Administration-approved combination medication Orkambi®, which is used for treating cystic fibrosis. Experimental evidence suggests that lumacaftor can be used as a monotherapy to improve brain perfusion and memory in heart failure. To clinically assess this therapeutic intervention, a formulation with demonstrated bioequivalence to the currently approved combination product is required.

METHODS: This comparative bioavailability and food-effect study compared lumacaftor pharmacokinetics in healthy patients following: (i) oral administration of lumacaftor (400 mg; Test Product) or Orkambi® (lumacaftor 400 mg/ivacaftor 250 mg; Reference Product) in the fed state and (ii) oral administration of lumacaftor (400 mg; Test Product) in the fasted to fed state. Plasma lumacaftor concentrations were measured with a standard liquid chromatography with tandem mass spectrometry approach.

RESULTS: The "Test-to-Reference ratio" of the geometric least-square means for maximum plasma concentration and area under the curve met the Food and Drug Administration-defined criteria for bioequivalence; median times to maximum plasma concentration values were not statistically different. The "Fed to Fasted ratio" of the geometric least-square means for maximum plasma concentration and area under the curve indicated a clear food effect on bioavailability. Lumacaftor exposure was approximately two times higher when administered with fatty foods than when taken in a fasting state. The monosubstance formulation was well tolerated.

CONCLUSIONS: We conclude that the lumacaftor monosubstance formulation delivers lumacaftor exposure that is not meaningfully different than the currently approved combination product.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05968612.

PMID:40551045 | DOI:10.1007/s40268-025-00514-9

PLoS One. 2025 Jun 23;20(6):e0325347. doi: 10.1371/journal.pone.0325347. eCollection 2025.

ABSTRACT

BACKGROUND: Non-tuberculous mycobacteria (NTM) are pulmonary pathogens with increasing incidence and prevalence worldwide, with people with cystic fibrosis (pwCF) traditionally considered at high risk of disease development. The imaging assessment of NTM-pulmonary disease (NTM-PD) relies heavily on high-resolution computed tomography (HRCT). However, due to lengthy treatment regimens and the need for long-term follow-up, serial HRCT's result in progressive exposure to ionizing radiation; a particular concern in younger people.

METHODS: We performed a retrospective cohort study of patients who had undergone serial thoracic magnetic resonance imaging (tMRI) scans to monitor NTM-PD as a novel tool to image the lung with a view to creating an algorithm for the utility of tMRI in the management of NTM-PD.

RESULTS: Thirty-six patients, of which twenty-four had a diagnosis of CF, with suspected or confirmed NTM-PD underwent serial tMRI between 1st January 2013 and 30th June 2018. A total of 117 serial tMRI's were performed (mean number per patient 3.25; range 2-6). The associated clinical impact that each serial MRI had on management, deemed as the utility of tMRI, found that all tMRI's were classified as aiding management with 60 (51.3%) altering management. tMRI's were more likely to alter management in the non-CF cohort than the CF cohort (69.4% vs. 43.2%). No imaging-related adverse events were reported across the 117 tMRI's.

CONCLUSION: This study highlights that tMRI may hold promise as a monitoring tool in NTM-PD and should be prospectively evaluated in the monitoring of individuals with NTM-PD.

PMID:40549769 | DOI:10.1371/journal.pone.0325347

Access Microbiol. 2025 Jun 20;7(6):000979.v3. doi: 10.1099/acmi.0.000979.v3. eCollection 2025.

ABSTRACT

Non-typeable Haemophilus influenzae (NTHi) is an early pathogen isolated from the lungs of children with cystic fibrosis (CF). However, its role in the progression of CF lung infection is poorly understood. Additionally, whether it forms biofilms in the lungs of people with CF is an open question. The development of synthetic CF sputum media (SCFM) has given key insights into the microbiology of later CF pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, through replicating the chemical composition of CF sputum. However, the growth of NTHi in these media has not previously been reported. We show that NTHi grows poorly in three variants of SCFM commonly used to induce in vivo-like growth of P. aeruginosa and S. aureus (SCFM1, SCFM2 and SCFM3). The addition of NAD and haemin to SCFM1 and SCFM2 promoted the planktonic growth and biofilm formation of both laboratory and clinical NTHi isolates, and we were able to develop a modified variant of SCFM2 that allows culture of NTHis. We show that NTHi cannot be identified in an established ex vivo model of CF infection, which uses SCFM and porcine bronchiolar tissue. This may in part be due to the presence of endogenous bacteria on the pig lung tissue, which outcompete NTHi, but the lack of selective agar to isolate NTHi from endogenous bacteria, and the fact that NTHi is an exclusively human pathogen, makes it hard to conclude that this is the case. Through spiking modified SCFM2 with filter-sterilized lung homogenate, biofilm growth of clinical NTHi isolates was enhanced. Our results highlight that there are crucial components present in the lung tissue, which NTHi require for growth, which are not present in any published variant of SCFM from the Palmer et al. Endres and Konstan in JAMA (2022;137:191-1) lineage. Our results may inform future modifications to SCFM recipes to truly mimic the environment of CF lung sputum and thus, to facilitate the study of a wide range of CF pathogens.

PMID:40548129 | PMC:PMC12181625 | DOI:10.1099/acmi.0.000979.v3

New Microbes New Infect. 2025 May 28;66:101601. doi: 10.1016/j.nmni.2025.101601. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Burkholderia cepacia complex (BCC) is a group of multi-drug resistant (MDR) pathogens that are challenging to treat, especially in cystic fibrosis (CF) patients. Ceftazidime-avibactam is a promising antibiotic combination for treating BCC infections, but its efficacy requires further in vitro evaluation.

METHODS: This systematic review was conducted following the PRISMA guidelines to assess the in vitro susceptibility of BCC strains to ceftazidime-avibactam. We systematically searched PubMed, Web of Science, Scopus, and Embase databases. Inclusion criteria required original articles reporting on BCC susceptibility to ceftazidime-avibactam using standard antimicrobial susceptibility testing methods.

RESULTS: A total of 9 studies met the inclusion criteria. These studies were conducted between 2010 and 2024, with data from the USA, France, Germany, Belgium, and other countries. The studies used various methods, including agar dilution, broth microdilution, and disc diffusion. The minimum inhibitory concentration (MIC) range for ceftazidime-avibactam was found to vary, with the combination showing significantly improved susceptibility compared to ceftazidime alone.

CONCLUSION: This systematic review demonstrates that ceftazidime-avibactam significantly enhances the susceptibility of BCC strains, supporting its potential as an effective therapeutic option for BCC infections in CF patients. Further clinical studies are needed to confirm these findings and guide treatment strategies.

PMID:40547539 | PMC:PMC12182339 | DOI:10.1016/j.nmni.2025.101601

Ann Allergy Asthma Immunol. 2025 Jun 21:S1081-1206(25)00314-X. doi: 10.1016/j.anai.2025.06.024. Online ahead of print.

ABSTRACT

BACKGROUND: Nonspecific gastrointestinal symptoms associated with cystic fibrosis (CF) may be misdiagnosed as food allergy (FA). There is a paucity of data regarding prevalence and phenotype of IgE-mediated FA in CF.

OBJECTIVE: We aimed to determine the prevalence and characteristics of pediatric FA in CF.

METHODS: We conducted a retrospective pediatric cohort study using the Cystic Fibrosis Foundation Registries and electronic medical records from [redacted names A and B]. Demographic, biometric, and medical information were collected, and individuals suspected of having FA were identified through multiple inclusion criteria. A convincing FA diagnosis was established based on a priori criteria including medical history, testing results, and management. Estimated prevalence was calculated as a percentage and compared to the most recently reported pediatric FA prevalence in the United States (US).

RESULTS: Among 289 patients (51.21% male, median age=12.40 years), 11 (3.81%, 95% confidence interval [CI] 1.91-6.71) had at least one convincing FA, yielding a smaller prevalence than the most recent estimate in the US pediatric population (7.60%, 95% CI 7.10-8.10, p=0.015). Male CF patients (6.08% versus 1.42%, p=0.038) and patients without pancreatic enzyme replacement (9.09% versus 2.25%, p=0.020) had higher prevalence of convincing FA.

CONCLUSION: Our study of pediatric CF patients found a lower prevalence of FA compared to the general pediatric population in the US. Stringent criteria should be used when labeling CF patients with FA to minimize overdiagnosis. Further studies are needed to investigate if CF could potentially be protective against the development of FA.

PMID:40550267 | DOI:10.1016/j.anai.2025.06.024

Clin Ther. 2025 Jun 21:S0149-2918(25)00184-5. doi: 10.1016/j.clinthera.2025.05.016. Online ahead of print.

ABSTRACT

PURPOSE: Elexacaftor/tezacaftor/ivacaftor (ETI) is an efficacious targeted therapy for cystic fibrosis, but its impact on the use of maintenance therapies has not been assessed in Australia.

METHODS: We performed a retrospective cohort study including individuals with at least 1 ETI dispensing. Quarterly prevalence of airway therapies, antibiotics, and gastrointestinal and endocrine medications was evaluated 24 months before and after ETI initiation. Odds ratios for dispensing were estimated using mixed-effects logistic regression.

FINDINGS: Airway therapies and oral/inhaled antibiotic use declined after ETI, whereas gastrointestinal and endocrine therapies remained stable.

IMPLICATIONS: Elexacaftor/tezacaftor/ivacaftor is associated with a reduced treatment burden in cystic fibrosis, supporting broader access.

PMID:40545418 | DOI:10.1016/j.clinthera.2025.05.016

Rev Iberoam Micol. 2025 Apr 4:S1130-1406(25)00019-1. doi: 10.1016/j.riam.2025.02.004. Online ahead of print.

ABSTRACT

Solid organ transplant (SOT) recipients have a higher risk of developing invasive fungal infection (IFI). Isavuconazole is a novel broad-spectrum azole active against Aspergillus and Mucor. Isavuconazole is well tolerated, shows an excellent bioavailability and predictable pharmacokinetics, good diffusion to tissues, significantly reduced drug-drug interactions with immunosuppressive drugs in comparison with other broad-spectrum azoles, and few serious adverse effects, including hepatic toxicity. We have performed an extensive literature review concerning the clinical experience on the use of isavuconazole in SOT as prophylaxis and treatment of IFI, which included the SOTIS and the ISASOT studies, and fourteen published case reports. Clinical response, all-cause and invasive aspergillosis-attributable mortality in recipients treated with isavuconazole were similar to those described with voriconazole. Drug-drug interactions with immunosuppressive agents were manageable after the adjustment of tacrolimus and mTOR inhibitors. Isavuconazole showed fewer drug-related side effects and a smaller rate of premature discontinuation than voriconazole. In conclusion, isavuconazole appears to be a reasonable option for the treatment of IFI in SOT, and can be an alternative to voriconazole as antifungal prophylaxis in lung transplantation. Nonetheless, more clinical studies are needed.

PMID:40545388 | DOI:10.1016/j.riam.2025.02.004

Mol Ther. 2025 Jun 21:S1525-0016(25)00453-8. doi: 10.1016/j.ymthe.2025.06.002. Online ahead of print.

NO ABSTRACT

PMID:40544842 | DOI:10.1016/j.ymthe.2025.06.002

Leg Med (Tokyo). 2025 Jun 6;76:102653. doi: 10.1016/j.legalmed.2025.102653. Online ahead of print.

ABSTRACT

Deoxyribonucleases (DNases) are essential enzymes involved in DNA metabolism, playing critical roles in replication, repair, recombination, and the degradation of apoptotic DNA. They are primarily classified into two families: DNase I and DNase II, each exhibiting distinct catalytic properties and tissue-specific functions. Dysregulated DNase activity is implicated in various diseases. This review synthesizes current knowledge on the biochemical properties, gene structures, tissue distributions, and clinical significance of DNases. It explores their roles in disease mechanisms, the impact of genetic polymorphisms on enzyme activity, and their potential as biomarkers for early disease detection. While considerable progress has been made in elucidating the physiological functions of endogenous DNases, increasing attention is being directed toward the therapeutic applications of exogenous DNases. Beyond their established role in cystic fibrosis treatment, DNases show promise in addressing conditions such as cancer, acute kidney injury, sepsis, traumatic brain injury, and diabetic wound healing by modulating inflammation and clearing extracellular DNA. By providing a comprehensive overview of DNase families, this review highlights their functional diversity and clinical relevance, paving the way for future research, therapeutic advancements, and novel approaches to disease management. Therefore, this article contributes valuable insights not only to the field of legal medicine but also to broader areas of basic and clinical medical sciences.

PMID:40544556 | DOI:10.1016/j.legalmed.2025.102653

Cell Death Discov. 2025 Jun 21;11(1):286. doi: 10.1038/s41420-025-02571-0.

ABSTRACT

Fanconi anemia (FA) is caused by mutations affecting FANC genes involved in DNA repair, with nearly 20% of FA patients harboring nonsense mutations. Ataluren (PTC124) is a translational read-through-inducing drug (TRID) already approved in Europe that has a well-established safety profile even in pediatric patients. Amlexanox, an anti-inflammatory drug, also promotes read-through of premature stop codons caused by nonsense mutations. We compared ataluren and amlexanox in rescuing FANCA, FANCC and FANCF protein synthesis in lymphoblastoid cell lines and fibroblasts obtained from FA patients with nonsense mutations. While ataluren restored all FANC protein levels, amlexanox was partially effective only on FANCA. Notably, the rescue of FANC proteins resulted in a significant downregulation of p53. Moreover, unlike amlexanox, ataluren remarkably improved cell viability and reduced chromosomal aberrations upon exposure to genotoxic compounds. Amlexanox primarily reduced the signal transducer and activator of transcription 2 (STAT2) phosphorylation. Furthermore, FANCA-mutated fibroblasts exhibited a higher frequency of micronuclei formation as well as lower lamin B1 expression compared to their gene-edited counterpart re-expressing wild-type FANCA. Interestingly, ataluren significantly limited the generation of micronuclei in nonsense-mutated primary FANCC fibroblasts, restoring lamin B1 expression. This study represents a milestone of drug development for FA as it paves the way for clinical development of TRIDs, indicating ataluren as a promising approach to address the genetic instability and reduce the risk of malignant transformation in FA cells. Moreover, these results highlight the importance of a reliable experimental pipeline to assess whether minimal protein rescue via translational read-through can yield meaningful phenotypic rescue.

PMID:40544182 | DOI:10.1038/s41420-025-02571-0

J Cyst Fibros. 2025 Jun 20:S1569-1993(25)01515-2. doi: 10.1016/j.jcf.2025.06.001. Online ahead of print.

ABSTRACT

BACKGROUND: Clinical data regarding in utero exposure to CFTR modulators (CFTRm) are limited. Our objective was to describe pregnancy outcomes, with particular attention to malformations, and neonatal adverse outcomes among prospective pregnancies exposed to CFTRm, using clinical data from the French Network of Pharmacovigilance Centres and the Teratology Information Service CRAT (Centre de Reference sur les Agents Tératogènes).

METHODS: An observational multicentre study was performed on the reported CFTRm-exposed pregnancies with an expected delivery date between 2018 and 2023. We described prospective cases, defined as pregnancies for which the outcome was unknown and no adverse prenatal outcome was diagnosed at the time of first contact with the healthcare professional. Major congenital anomalies (MCA) were classified according to criteria of the European Registration of Congenital Anomalies and Twins.

RESULTS: Fifty-eight pregnancies were included, mainly exposed to elezacaftor/tezacaftor/ivacaftor throughout pregnancy (87.9 %).There were 53 live births, four spontaneous abortions and one medical abortion (fetus with cystic fibrosis). One atrial septal defect and one acrania/anencephaly were observed, resulting in a MCA prevalence of 3.4 % (IC95 %: 0.4- 11.9). There were three neonatal adverse outcomes without a clearly identified cause: one sudden massive alveolar hemorrhage, one delayed respiratory distress and one delayed transient hypotonia. No cataract was found in children who had an ophthalmological examination (n = 10).

CONCLUSIONS: This prospective case series - the largest to date - does not suggest a high rate of MCA or neonatal adverse outcomes in CFTRm-exposed pregnancies. Further studies including long-term follow-up of in utero exposed children are needed to confirm these findings.

PMID:40544114 | DOI:10.1016/j.jcf.2025.06.001

Diabetes Metab. 2025 Jun 4:101667. doi: 10.1016/j.diabet.2025.101667. Online ahead of print.

ABSTRACT

AIM: People living with type 1 diabetes (T1D) are at elevated risk of additional autoimmune diseases (ADs) than the general population. We aimed to describe the association between additional ADs and T1D-related physical and mental burden in adults.

METHODS: This was a cross-sectional analysis using data from the BEhaviors, Therapies, TEchnologies, and hypoglycemic Risk in T1D (BETTER) registry. Using patient reported-outcomes and validated questionnaires, we compared prevalence of vascular complications, hypoglycemia, and mental health issues between those with T1D alone (AD-) and T1D with additional AD (AD+).

RESULTS: Among 3222 participants (66.2 % female, 42.7 ± 15.0 years), 36.3 % reported ≥ 1 AD+. The AD+ group was older (+4.4 years) and more female (+17.7 %) than the AD- group. The AD+ group had similar HbA1c (P = 0.20) but was more likely to report level 2 hypoglycemia in the past month (OR: 1.27 [95 %Cl 1.06-1.52]) and level 3 hypoglycemia since diagnosis (1.22 [1.05-1.42]). The AD+ group reported more cardiovascular disease (1.40 [1.03 to 1.90]), nephropathy (1.49 [1.19-1.86]), neuropathy (1.38 [1.13-1.69]), retinopathy (1.48 [1.22-1.78]), higher depression scores (p = 0.015), and anxiety/depression medication use (1.31 [1.10-1.56]). Number of AD+ was positively associated with depression scores (1 AD+ P = 0.055, 2+ AD+ p = 0.027), level 3 hypoglycemia since diagnosis (1 AD+ p = 0.037, 2+ AD+ P = 0.025), and number of chronic complications (1 AD+ P < 0.001, 2+ AD+ P < 0.001).

CONCLUSION: For people with T1D, living with additional ADs is associated with higher levels of physical and mental diabetes complications, warranting regular screening in this population.

PMID:40544067 | DOI:10.1016/j.diabet.2025.101667

Lancet Infect Dis. 2025 Jun 17:S1473-3099(25)00224-5. doi: 10.1016/S1473-3099(25)00224-5. Online ahead of print.

ABSTRACT

BACKGROUND: Only a small number of antifungal therapies for invasive fungal disease (IFD) are currently available, and many pathogens are resistant to one or more of these therapies. Olorofim, the first orotomide antifungal agent to be developed, is active against fungi that are resistant to registered therapies. It impairs fungal pyrimidine biosynthesis, leading to cell death. We sought initial data on the efficacy and safety of olorofim as a therapy for IFD.

METHODS: In this single-arm, open-label, phase 2b study, patients aged 16 years or older with few or no treatment options for proven IFD or probable invasive pulmonary aspergillosis were recruited from 22 centres in 11 countries. The first 58 patients received a weight-based loading dose of oral olorofim 180-300 mg in two to three divided doses on day 1 followed by 120-240 mg daily in two to three divided doses from day 2 onwards. On the basis of pharmacokinetic data from the first 25 patients, dosing was simplified from patient 59 onwards to a loading dose of 150 mg twice on day 1 followed by a fixed maintenance dose of 90 mg twice a day up to day 84 (main treatment phase) with extended therapy as needed. The primary endpoint was global response rate (based on a composite of clinical, radiological, and mycological responses) at day 42, determined as success (complete or partial improvement in all three components) or failure (stable disease or progression on any one component or death from any cause) by a data review committee (DRC). Secondary efficacy endpoints included global response rate at day 84 and all-cause mortality at day 42 and day 84. Global response rate with stable disease classified as success and response rate in the clinical component of the global response at day 42 and day 84 were also assessed. Efficacy was analysed for all patients who were confirmed by the DRC to have an IFD and who received at least one dose of olorofim (the modified intention-to-treat population). Safety was analysed in all patients who received at least one dose of olorofim (the safety population). This trial is registered with ClinicalTrials.gov, NCT03583164, and is completed.

FINDINGS: Between June 6, 2018, and Sept 8, 2022, 204 patients were enrolled. Of these, 203 were treated with olorofim and 202 (124 male, 78 female) had DRC-adjudicated IFD. Causative pathogens were Aspergillus spp (n=101, including 22 azole-resistant strains), Lomentospora prolificans (n=26), Scedosporium spp (n=22), Coccidioides spp (n=41), and other fungi (n=12). Successful global response was confirmed in 58 of 202 patients (28·7%, 95% CI 22·6-35·5) at day 42 and in 55 patients (27·2%, 21·2-33·9) at day 84. Successful global response with stable disease included in the definition of success was seen in 152 patients (75·2%, 68·7-81·0) at day 42 and in 128 patients (63·4%, 56·3-70·0) at day 84. A successful clinical response was seen in 121 patients (59·9%, 52·8-66·7) at day 42 and in 109 patients (54·0%, 46·8-61·0) at day 84. All-cause mortality was documented in 24 patients (11·9%, 7·8-17·2) at day 42 and in 33 patients (16·3%, 11·5-22·2) at day 84. Mean dosing duration was 73 days (SD 25) for the 203 patients in the main treatment phase (median 84 days [range 2-99, IQR 78-87]) and 361 days (SD 220) for the 114 patients who received extended treatment after the main phase (median 309 days [38-988, 180-502]). Medically significant liver enzyme elevations adjudicated to be at least possibly due to olorofim occurred in 20 (10%) of 203 patients and were managed to resolution by dose modification in 14 (7%) patients or by discontinuation of treatment in six (3%). Gastrointestinal intolerance, which occurred in 20 (10%) patients, was predominantly reported as mild or moderate and self-limiting. There were no treatment-related deaths.

INTERPRETATION: Olorofim showed efficacy and good tolerability in patients with IFD with few or no treatment options. Further studies will be needed to fully delineate the role of this new antifungal agent.

FUNDING: F2G.

PMID:40541222 | DOI:10.1016/S1473-3099(25)00224-5

Respir Med Res. 2025 May 29;88:101184. doi: 10.1016/j.resmer.2025.101184. Online ahead of print.

ABSTRACT

BACKGROUND: Rehabilitation has been shown to enhance patient performance before and after lung transplantation, but limited data exist on its role during the immediate post-transplant phase in critical care units.

METHODS: We conducted a single-center retrospective study. All adult patients who underwent bilateral transplantation for cystic fibrosis were included. Patients were followed from admission to discharge from critical care. All rehabilitation sessions were recorded. We aimed to evaluate the relationship between the amount of mobilization performed by the patient in critical care, and functional performance at discharge.

RESULTS: We included 36 patients (21 males) with a median age of 29 years (IQR: 24.5-35.0) and a median critical care length of stay of 15 days (12.5-20). Patients performed a total of 388 sessions of rehabilitation. Out-of-bed mobilization started at a median of post-operative day 2.5 (IQR: 1.0-4.5), with the first walking session at day 3 (IQR: 2.0-4.5). A strong correlation was found between daily walking distance and functional performance, as measured by the 6-minute walk test, with a Pearson correlation coefficient of 0.70 (95 % CI: 0.48-0.84).

CONCLUSIONS: After lung transplantation for cystic fibrosis, early initiated rehabilitation in critical care is feasible and can improve patients' functional performance. These findings are promising, but require validation in other lung transplant populations.

PMID:40540974 | DOI:10.1016/j.resmer.2025.101184

Am J Respir Cell Mol Biol. 2025 Jun 20. doi: 10.1165/rcmb.2024-0597MA. Online ahead of print.

ABSTRACT

Transplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary- and pluripotent stem cell (PSC)-derived basal cells to efficiently engraft into the mouse trachea after injury. However, there are many hurdles to overcome in translating these approaches to humans including developing safe and efficient methods for delivery in larger animal models. We propose a model which targets preconditioning and cell-delivery to intrapulmonary airways utilizing a micro-bronchoscope for delivery. The detergent polidocanol was adapted for distal lung pre-conditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24-hours post-delivery. While initial re-epithelialization of airways occurred later than tracheas, complete repair was observed within 7-days. Both PSC-derived and primary basal cells delivered via micro-bronchoscope post-polidocanol injury engrafted in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted pre-conditioning and cell delivery to the conducting intra-pulmonary airways. Thus providing an important framework for pre-clinical translation of approaches for engineered airway epithelial regeneration.

PMID:40540686 | DOI:10.1165/rcmb.2024-0597MA

Ann Am Thorac Soc. 2025 Jun 20. doi: 10.1513/AnnalsATS.202501-103OC. Online ahead of print.

ABSTRACT

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) provided substantial health benefits to children with cystic fibrosis (CF) in clinical trials; there is less information about its effectiveness in a "real world" setting. Methods: The pediatric PROMISE substudy enrolled CF children 6 to <12 years of age starting ETI. Outcomes measured at baseline (pre-ETI), 1, 3, 6 and 12 months after ETI initiation included the lung clearance index (LCI2.5), % predicted forced expiratory volume in 1 second (ppFEV1), the CFQ-R respiratory domain symptom score (CFQ-R RD), height, weight, oropharyngeal (OP) cultures, culture and DNA-based analysis of sputum microbiology (when sputum available). Sweat chloride was assessed at baseline, 1 and 6 months. Results: 125 participants were enrolled at 20 US CF centers. Lung function improvement post-ETI initiation was rapid and sustained through 12 months, with a mean decrease in LCI2.5 of -0.79 (95% CI -1.04, - 0.55) and a mean increase in ppFEV1 of 5.6 (95% CI 3.4, 7.7). Respiratory symptoms also improved significantly (mean change in CFQ-R RD of 4.1 (95% CI [1.94, 6.24]). Sweat chloride decreased significantly at 6 months (mean change -47.2 mmol/L (95% CI -51.99, -43.8)). Weight, BMI and height z scores were not different from baseline at 12 months. S. aureus prevalence in OP or sputum cultures did not change but its density in sputum cultures decreased a mean of 1.47 log10 CFU/g (95% CI -2.37, -0.58) at 12 months. Conclusions: Initiation of ETI in a real-world setting was associated with clinically significant improvements in lung function and symptoms, and decreased S. aureus sputum density at one year; lung function improvements were smaller than those reported in clinical trials.

PMID:40540670 | DOI:10.1513/AnnalsATS.202501-103OC

Pancreas. 2025 Jun 23. doi: 10.1097/MPA.0000000000002522. Online ahead of print.

ABSTRACT

BACKGROUND: The advent of highly effective modulator therapies (HEMT), namely elexacaftor, tezacaftor and ivacaftor (ETI), has resulted in substantial improvements in lung function, growth, and quality of life, for people with cystic fibrosis (PwCF). However, the understanding of the impact of ETI on gastrointestinal (GI) disease burden is evolving. This study aims to describe and compare the prevalence of GI manifestations, prescribed GI medications, and GI procedures between two time periods pre and post-ETI approval in children with CF (CwCF).

METHODS: This is a retrospective cohort study utilizing TriNetX, a multicenter database. The study includes patients between 6 to 21 years old with ICD-10 diagnostic codes for CF and a prescription for pancreatic enzyme replacement therapy (PERT) to match disease severity. We included 4 years before and 4 years after the release of ETI combination therapy.

RESULTS: When comparing CwCF taking PERT, on or off ETI, the prevalence of diagnostic codes for chronic pancreatitis, constipation, unspecified noninfective gastroenteritis, and colitis significantly decreased after ETI use (all P < 0.0001). The prevalence of other luminal disorders, liver disorders, and acute pancreatitis did not differ between the two groups. The prevalence of prescribed medications including mucolytics, vitamins, PPI, and antidiarrheal was similar for both groups except for a reduction in prescribed laxatives (p-value = 0.0001). The prevalence of GI procedures was also similar in both groups.

CONCLUSION: The reduction in constipation and non-infective gastroenteritis and colitis is important as GI symptoms are linked to the quality of life of CwCF. There remains a great clinical need to evaluate the effects of ETI on GI disorders, especially as the age of initial use of this therapy decreases, and the duration of use increases.

PMID:40540361 | DOI:10.1097/MPA.0000000000002522

ACS Chem Biol. 2025 Jun 20. doi: 10.1021/acschembio.5c00157. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) pharmacological correctors improve the cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side effects of these correctors and adverse drug interactions have been reported, emphasizing the need to understand off-targets. We synthesized VU439, a functionalized photoaffinity ligand (PAL) of VX-445. Chemoproteomics analysis by mass spectrometry (MS) was used to identify cross-linked proteins in CF bronchial epithelial cells expressing F508del CFTR. We identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), an uncharacterized putative oxidoreductase, as a VX-445-specific off-target. We also characterized changes in the metabolomic profiles of cells overexpressing SCCPDH to determine the consequence of binding of VX-445 to SCCPDH. These data show dysregulation of amino acid metabolism and a potential inhibitory activity of VX-445 on SCCPDH. The identified off-target may explain the exacerbation of psychological symptoms observed in the clinic, thus emphasizing the need for further optimization of correctors.

PMID:40539870 | DOI:10.1021/acschembio.5c00157

Microbiol Spectr. 2025 Jun 20:e0071925. doi: 10.1128/spectrum.00719-25. Online ahead of print.

ABSTRACT

Mycobacterium abscessus presents significant clinical challenges due to its intrinsic and acquired resistance to antibiotics, resulting in prolonged treatments and poor patient outcomes. Addressing the urgent need for novel therapeutics, this study explores the antimicrobial potential of VLX600, originally developed as an anticancer agent, against M. abscessus. Screening a library of 3,200 clinically evaluated compounds identified VLX600 as a potent antimicrobial with minimal cytotoxicity. VLX600 demonstrated inhibitory effects against various strains of M. abscessus with minimum inhibitory concentrations of 4 µg/mL-16 µg/mL. It also remained effective in intracellular M. abscessus in host cells and exhibited broad-spectrum activity against other bacterial species, including Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The antimicrobial activity of VLX600 was abrogated by supplemental iron, indicating a mechanism dependent on iron chelation. VLX600 significantly reduced bacterial burdens and inflammation in a murine model of pulmonary M. abscessus infection. Additionally, synergistic effects were observed when VLX600 was combined with conventional antibiotics such as amikacin and clarithromycin in vitro. These findings highlight VLX600 as a promising candidate for repurposing as an antimicrobial agent against M. abscessus, warranting further clinical investigations.IMPORTANCEMycobacterium abscessus is an opportunistic pathogen that commonly causes pulmonary infections in cystic fibrosis patients. These infections are notoriously difficult to treat due to high levels of antibiotic resistance of M. abscessus, resulting in low cure rates. In this study, we identified a novel antibiotic candidate, VLX600, through high-throughput screening of 3,200 clinical compounds and demonstrated that VLX600 inhibits the growth of M. abscessus by depriving it of ferric and ferrous ions. This study highlights the potential of iron chelators as antimicrobial agents against M. abscessus infections. Since iron is an essential nutrient for the growth of many bacteria, the use of iron chelators could be extended to other infectious diseases. We hope this research will inspire further studies aimed at developing iron chelators as a novel class of antimicrobial agents.

PMID:40539807 | DOI:10.1128/spectrum.00719-25

Pediatr Pulmonol. 2025 Jun;60(6):e71166. doi: 10.1002/ppul.71166.

ABSTRACT

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) is a breakthrough therapy for cystic fibrosis (CF). We aimed to assess ETI's real-world impact on peripheral airway disease assessed as ventilation distribution inhomogeneity using nitrogen multiple breath washout (N2MBW) in children aged 6-17 years. Additionally, we compared the two outcomes, lung clearance index (LCI), and ventilation distribution efficiency (VDE), as VDE is considered to adjust for a theoretical overestimation of lung disease when using LCI.

METHODS: This nationwide study included data from N2MBW performed during routine clinical care. Linear mixed effect regression was used to assess changes in LCI and VDE after 12 months of ETI treatment. Subgroup analyses included baseline age (6-11 vs. 12-1 years) and disease severity (normal-moderate vs. severe-very severe).

RESULTS: We included 131 children (78% homozygous for F508del mutation, mean [SD] age 11.5 [3.4]), and 339 N2MBW tests. The median (range) number of tests per child was 3 (1-10). The estimated mean (95% CI) 12-months post-ETI improvement in LCI and VDE were 1.7 units (-2.1; -1.2, p < 0.001) and 2.1%-point (1.6; 2.6, p < 0.001), respectively. Similar LCI and VDE improvements were observed across age groups. Using VDE, fewer children were categorized with very severe lung disease, and the ETI-effect did not differ between the severity groups, unlike LCI.

CONCLUSION: Our research demonstrates that ETI treatment significantly improves lung function, as measured by N2MBW, in Danish children and adolescents with CF. VDE improvements were consistent across age and disease severity groups. In contrast, LCI revealed larger effect estimates for those with severe to very-severe lung impairment.

PMID:40539675 | DOI:10.1002/ppul.71166