The orally inhaled route of administration for respiratory indications can maximize drug exposure to the site of action (lung) to increase efficacy while minimizing systemic exposure to achieve an improved safety profile. However, due to the difficulty of taking samples from different regions of the human lung, often only systemic pharmacokinetic (PK) samples are taken and assumed to be reflective of the lung PK of the compound, which may not always be the case. In this study, a mechanistic lung physiologically based pharmacokinetic (PBPK) model was built using a middle-out approach (i.e., combining elements of bottom-up prediction and using clinical data to inform some model parameters) to predict plasma and lung PK of an orally inhaled TMEM16A potentiator GDC-6988 in humans. The lung PBPK model accounted for lung deposition, lung and oral absorption, systemic clearance, and tissue distribution. The model was refined using data from a Phase 1b study with dry powder (DP) formulation and was also verified using data from a Phase 1 study with a nebulized (Neb) formulation. The refined model adequately captures the observed GDC-6988 plasma PK profiles in both the DP and Neb studies and allows prediction of the regional lung fluid and tissue concentrations. The sensitivity analyses showed that the systemic Cmax depended on the ratio of airway to alveolar deposition, but this did not impact the AUC. This novel mechanistic lung PBPK modeling framework could be applied to predict plasma and regional lung exposure and inform the early clinical development of inhaled molecules (e.g., dose selection).

Lenabasum is a cannabinoid receptor 2 (CB2) agonist under development for cystic fibrosis (CF), targeting inflammation. We evaluated the efficacy and safety of lenabasum in people with CF (pwCF).

We conducted a global, 28-week, randomized, double-blind, placebo-controlled Phase 2b trial. PwCF were ≥12 years old with 2-3 pulmonary exacerbations (PEx) treated with intravenous (IV) antibiotics (or 1 PEx treated with IV and ≥1 PEx treated with oral antibiotics) in the past year. Subjects were randomized 2:1:2 to lenabasum 20 mg BID, lenabasum 5 mg BID, or placebo BID. Primary endpoint was rate of PEx, comparing lenabasum 20 mg BID to placebo.

Among 447 subjects from 21 countries, mean age was 26.9 (10.3 SD) years, 53.6% were female, 45.2% homozygous for F508del, and 24.9% received CFTR modulators. Highest ppFEV1 in the previous year was 69.2% with the majority having 1-2 PEx treated with IV antibiotics (2-7 PEx treated with either IV or oral antibiotics). PEx incidence over 28 weeks was 0.84 for placebo, 0.75 for lenabasum 5 mg BID, and 0.91 for lenabasum 20 mg BID; rates were not lower relative to placebo in the 5 mg (incidence rate ratio (IRR)=0.89, 95% CI 0.66 to 1.19, p = 0.44) or the 20 mg group (IRR 1.08, 95% CI 0.86 to 1.37, p = 0.51). PEx occurred less frequently in participants from Eastern Europe, but there was no evidence of regional variation in treatment efficacy. Lenabasum was well tolerated, without safety signals.

Lenabasum did not improve key clinical outcomes in this Phase 2b study in pwCF.

Flexible wearable potentiometric ion sensors for continuous monitoring of electrolyte cations have made significant advances in bioanalysis for personal healthcare and diagnostics. However, less attention is paid to the most abundant extracellular anion, chloride ion (Cl-) as a mark of electrolyte imbalance and an important diagnostic indicator of cystic fibrosis, which has important significance for accurate monitoring in complex biological fluids. An all-solid-state Cl--selective electrode is constructed utilizing oxygen vacancies reinforced vanadium oxide with a nitrogen-doped carbon shield as the solid contact (V2O3-x@NC/Cl--ISE). The prepared V2O3-x@NC/Cl--ISE exhibits a low detection limit of 10-5.45 M without an interfacial water layer and shows a highly stable potential with 7.24 μV/h during 24 h, which is attributed to the rapid interfacial electron transfer of the conductive carbon layers and the valence state transition of the polyvalent vanadium center in charge storage processes. Additionally, the custom flexible sensing patch presents an excellent sensitivity retention rate under bending (95%) and twisting (93%) strains and possesses good anti-interference performance (ΔE < 8 mV) against common interfering ions and organic substances in sweat. Real-time monitoring of the Cl- concentration in sweat aligns with ion chromatography analysis results. This study presents a compact wearable Cl- monitoring platform for the easy tracking of exercise-induced dehydration and cystic fibrosis screening with promising applications in smart healthcare.

Inflammatory lung diseases (ILDs) represent a global public health crisis characterized by escalating prevalence, significant morbidity, and substantial mortality. In response to the complex immunopathogenic mechanisms driving these conditions, novel pharmacological strategies targeting resolution pathways have emerged throughout the discovery of specialized pro-resolving lipid mediator (SPM; resolvins, maresins, and protectins) dysregulation across the ILD spectra, positioning these endogenous molecules as promising therapeutic candidates for modulating maladaptive inflammation and promoting tissue repair. Over the past decade, this paradigm has catalyzed extensive translational research into SPM-based interventions as precision therapeutics for respiratory inflammation. In asthma, they reduce mucus hypersecretion, bronchial hyperreactivity, and airway inflammation, with prenatal SPM exposure potentially lowering offspring disease risk. In COPD, SPMs attenuate amyloid A-driven inflammation, normalizing cytokine/chemokine imbalances and oxidative stress and mitigating COVID-19-associated cytokine storm, enhancing survival. This review synthesizes SPMs' pharmacotherapeutic mechanisms in ILDs and evaluates current preclinical and clinical evidence.

People with CF (pwCF) have a significant risk for pulmonary infections with non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus (Mab). Mab is an emerging pathogen, which causes pulmonary infections in patients with chronic lung diseases, particularly CF; Mab pulmonary disease leads to progressive pulmonary dysfunction and increased morbidity and mortality. Despite advances in CF care, including CFTR modulators (CFTRm), Mab continues to pose a therapeutic challenge, with significant long-term medical burden. This review provides insights into the complex host-pathogen interplay of Mab infections in pwCF. It provides a detailed overview of Mab bacterial virulence factors, including biofilm formation, secretion systems, the virulence-associated rough morphotype, and antibiotic resistance mechanisms. This review also summarizes features conferring susceptibility of the CF host to Mab infections, alongside the contribution of the CF-host environment to the pathogenesis of Mab infection, such as antibiotic-derived microbial selection, within-host mycobacterial evolution, and interactions with co-pathogens such as Pseudomonas aeruginosa (PA). Finally, the therapeutic implications and novel treatments for Mab are discussed, considering the complex host-pathogen interplay.

Cystic fibrosis (CF) is a severe hereditary disease that affects multiple organ systems. Among these, the musculoskeletal system is an under-explored area. This interview study aimed to explore experiences of musculoskeletal symptoms and of manual therapies as complementary care in this context.

Semi-structured interviews were used to collect data from ten respondents. The data were subsequently analyzed through content analysis with an inductive approach in accordance with the method of Elo and Kyngäs.

The analysis resulted in three main categories; 1) Living with CF involves musculoskeletal health challenges, 2) Manual therapies impact daily life for people with CF, and 3) People with CF aspire for broader and more collaborative respiratory care.

The respondents described musculoskeletal symptoms in and around the thoracic cage. They experienced symptom relief and increased body awareness following manual therapy interventions (MTI) and recommended that these methods be offered as complementary care to enhance quality of life.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While CRISPR-based CFTR editing approaches have shown proof-of-concept for functional rescue in primary airway basal cells, induced pluripotent stem cells, and organoid cultures derived from patients with CF, their efficacy remains suboptimal. Here, we developed the CuFiCas9(Y66S)eGFP reporter system by integrating spCas9 and a non-fluorescent Y66S eGFP mutant into CuFi-8 cells, an immortalized human airway epithelial cell line derived from a patient with CF with homozygous F508del mutations. These cells retain the basal cell phenotype in proliferating cultures and can differentiate into polarized airway epithelium at an air-liquid interface (ALI), enabling both visualized detection of gene editing and electrophysiological assessment of CFTR functional restoration. Using this system, recombinant adeno-associated virus (rAAV)-mediated homology-directed repair (HDR) was evaluated in proliferating cultures. A correction rate of 13.5 ± 0.8% was achieved in a population where 82.3 ± 5.6% of cells were productively transduced by AAV.eGFP630g2-CMVmCh, an rAAV editing vector with an mCherry reporter. Dual-editing of F508del CFTR and Y66S eGFP was explored using AAV.HR-eGFP630-F508(g03) to deliver two templates and single guide RNAs. eGFP+ (Y66S-corrected) cells and eGFP- (non-corrected) cells were sorted via fluorescence-activated cell sorting and differentiated at an ALI to assess the recovery of CFTR function. Despite a low F508 correction rate of 2.8%, ALI cultures derived from the eGFP- population exhibited 25.2% of the CFTR-specific transepithelial Cl- transport observed in CuFi-ALI cultures treated with CFTR modulators. Next-generation sequencing revealed frequent co-editing at both genomic loci, with sixfold higher F508 correction rate in the eGFP+ cells than eGFP- cells. In both populations, non-homology end joining predominated over HDR. This reporter system provides a valuable platform for optimizing editing efficiencies in proliferating airway basal cells, particularly for development of strategies to enhance HDR through modulation of DNA repair pathways.

Mycobacterium abscessus (MABS) is an opportunistic pathogen that causes chronic, difficult-to-treat pulmonary infections, particularly in people with cystic fibrosis (PwCF), leading to rapid lung function decline and increased morbidity and mortality. Treatment is particularly challenging due to the pathogen's resistance mechanisms and the need for prolonged multidrug therapy, which is characterized by poor clinical outcomes and highlights the urgent need for novel therapeutic strategies. Imipenem/relebactam, a novel β-lactam-β-lactamase inhibitor combination, demonstrates in vitro activity against resistant MABS strains and effective pulmonary penetration. Prior research indicates synergistic activity of imipenem with various antibiotics against M. abscessus.

This study aims to evaluate the in vitro activity of imipenem/relebactam, alone and in combination with various antibiotics, against MABS clinical isolates from PwCF (n = 28).

Susceptibility and synergy were assessed using broth microdilution and checkerboard assays. Extracellular time-kill assays were performed to evaluate the bactericidal activity of synergistic three-drug combinations containing imipenem/relebactam.

Imipenem/relebactam demonstrated potent in vitro activity against clinical MABS isolates, exhibiting substantial synergy with cefuroxime, cefdinir, amoxicillin, and cefoxitin. Rifabutin, azithromycin, moxifloxacin, clofazimine, and minocycline also demonstrated additive effects with imipenem/relebactam. Extracellular time-kill assays identified imipenem/relebactam + cefoxitin + rifabutin and imipenem/relebactam + cefoxitin + moxifloxacin as the most effective combinations.

These findings suggest that imipenem/relebactam may offer a significant advancement in the management of MABS infections in PwCF. The promising efficacy of multidrug regimens combining imipenem/relebactam with agents like cefoxitin, azithromycin, moxifloxacin, clofazimine, and rifabutin highlights potential therapeutic strategies.

Chronic bacterial infections are responsible for significant morbidity and mortality in cystic fibrosis (CF) patients. Pseudomonas aeruginosa (Pa), the dominant CF pathogen, and Mycobacterium abscessus (Mab) can individually cause persistent, difficult to treat pulmonary infections. Co-infection by both pathogens leads to severe disease and poor clinical outcomes. Although interactions between Pa and other co-infecting pathogens in CF patients have been the focus of numerous studies, the dynamics of Pa-Mab interactions remain poorly understood.

To address this knowledge gap, the study examined how Mab and Pa influenced each other through culture-based growth assays and molecular-based dual RNAseq analysis. Growth was measured by CFU determination and luminescence reporter -based readouts.

In initial studies, we noted that the growth of Pa continued unimpeded in a planktonic co-culture model, whereas Pa appeared to exert a bacteriostatic effect on Mab. Strikingly, exposure of Mab to cell-free spent supernatant of Pa resulted in a dramatic, dose-dependent bactericidal effect. Initial characterization indicated that this potent Pa-derived anti-Mab cidal activity was mediated by a heat-sensitive, protease-insensitive soluble factor of >3kDa size. Further analysis demonstrated that expression of this mycobactericidal factor requires LasR, a central regulator of Pa quorum sensing (QS). In contrast, ΔLasR Pa was still able to exert a bacteriostatic effect on Mab during co-culture, pointing to additional LasR-independent factors able to antagonize Mab growth. However, the ability of Mab to adapt during co-culture to counter the cidal effects of a LasR regulated factor suggested complex interspecies dynamics. Dual RNAseq analysis of Mab-Pa co-cultures revealed significant transcriptional remodeling of Mab, with differential expression of 68% of Mab genes compared to minimal transcriptional changes in Pa. Transcriptome analysis reflected slowed Mab growth and metabolic changes akin to a non-replicating persister phase. A tailored Mab response to Pa was evident by enhanced transcript levels of genes predicted to counteract alkylquinolone QS signals, respiratory toxins, and hydrogen cyanide.

The study showed Mab is capable of coexisting with Pa despite Pa's antagonistic effects, eliciting an adaptive molecular response in Mab. This study provides the first transcriptome-level insight into genetic interactions between the two CF pathogens offering potential strategies for disrupting their communities in a CF lung to improve patient clinical performance. Moreover, identification of a novel antimicrobial natural product with potent cidal activity against Mab could lead to new drug targets and therapies for Mab infections.

In this review we discuss mucus, the viscoelastic secretion from goblet or mucous producing cells that covers and protects all non-keratinized wet epithelial surfaces. In addition to the surface of organs directly contacting with the external environment such as the eyes, this layer provides protection to the underlying gastrointestinal, respiratory and female reproductive tracts by trapping pathogens, irritants, environmental fine particles and potentially harmful foreign substances. Mucins, the primary structural components of mucus, form structurally different mucus layers at different sites in a process regulated by a variety of factors. Currently, more and more studies have shown that the mucus barrier is not only closely related to various intestinal mucus diseases, but also involved in the occurrence and development of various airway diseases and mucus-related diseases, thus it may become a new target for the treatment of various related diseases in the future. Since the dysfunction of the mucous layer is closely related to various pathological processes, in-depth understanding of its molecular mechanism and physiological role is of great theoretical and practical significance for disease prevention and treatment. Here, we discuss different aspects of the mucus layer by focusing on its chemical composition, synthetic pathways, and some of the characteristics of the mucus layer in physiological and pathological situations.

We aimed to investigate phenotypic and genomic traits of three Cupriavidus spp. isolates recovered from people with cystic fibrosis (PWCF). These bacteria are recognized as emerging pathogens in PWCF.

Using short and long sequencing reads, we assembled three hybrid complete genomes for the genus Cupriavidus, adding to the 45 published currently, describing multipartite genomes and plasmids. The isolates likely represent three different species, and they carry a cumulative total of 30 antibiotic resistance genes with high homology to well-characterized resistance determinants from other bacteria. Multidrug resistance to antibiotics used in CF management was observed in all three isolates. However, two treatments were active across all isolates: cefotaxime and piperacillin/tazobactam. Biofilm formation was only seen at physiological temperatures (37°C) and lost at 20°C and all isolates had low lethality in Galleria mellonella larvae. Isolates demonstrated variable motility, with one non-motile isolate carrying a disrupted flhD transcriptional regulator, abolishing flagella expression.

Our Cupriavidus spp. isolates showed considerable genomic and phenotypic variability that may impact their virulence and treatment in PWCF, where multidrug resistance will negate treatments and biofilm formation and motility play key roles in infection establishment, as seen in CF pathogens like Pseudomonas aeruginosa. More detailed investigation of clinical Cupriavidus isolates is needed for full understanding of the risk they pose to PWCF.

Rationale: Chronic Pseudomonas aeruginosa (Pa) airway infection is common and a key contributor to diminished lung function and early mortality in persons with cystic fibrosis (PwCF). Risk factors for chronic Pa among PwCF include CFTR (cystic fibrosis transmembrane conductance regulator) genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate Pa in most adolescents and adults with cystic fibrosis. Objectives: To identify new genetic modifiers contributing to the pathophysiology of chronic Pa infection in PwCF. Methods: A total of 4,945 participants in the CF Genome Project with whole-genome sequencing linked to longitudinal clinical data from the 2017 Cystic Fibrosis Foundation Patient Registry were used to conduct a time-to-event genome-wide association study using two definitions of chronic Pa infection. Results: We identified a genome-wide significant association (P = 2.2 × 10-8) between delayed onset of chronic Pa infection and rs194810, a common variant near the gene CHP2, which encodes calcineurin B homolog protein 2 (minor A allele frequency 43%). Survival curves by rs198410 allele dosage show that PwCF homozygous for the A allele are an average of 3 years older when achieving chronic Pa infection compared with G allele homozygotes. Conclusions: Variants near CHP2 are associated with a significant delay in the age of chronic Pa infection among PwCF.

Overactive neutrophilic inflammation causes damage to the airways and death in people with cystic fibrosis (CF), a genetic disorder resulting from mutations in the CFTR gene. Reducing the impact of inflammation is therefore a major concern in CF. Evidence indicates that dysfunctional NRF2 signaling in CF individuals may impair their ability to regulate their oxidative and inflammatory responses, although the role of NRF2 in neutrophil-dominated inflammation and tissue damage associated with CF has not been determined. Therefore, we examined whether curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF.

Combining Cftr-depleted zebrafish as an innovative biomedical model with CF patient-derived airway organoids (AOs), we aimed to understand how NRF2 dysfunction leads to abnormal inflammatory status and tissue remodeling and determine the effects of curcumin in reducing inflammation and tissue damage in CF.

We demonstrate that NFR2 is instrumental in regulating neutrophilic inflammation and repair processes in vivo, thereby preventing inflammatory damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin improves tissue repair by reducing CF-associated fibrosis. Our findings demonstrate that curcumin prevents CF-mediated inflammation via activating the NRF2 pathway.

This work highlights the protective role of NRF2 in limiting inflammation and injury and show that therapeutic strategies to normalize NRF2 activity, using curcumin or others NRF2 activators, might simultaneously reduce airway inflammation and damage in CF.

Pneumonia and parapneumonic effusion are uncommon in adults with CF. Clinical presentation and recovery may change following introduction of CFTR modulators (HEMT). Further prospective studies are needed. https://bit.ly/3BktB2N.

Cystic fibrosis (CF) is an autosomal recessive, chronic, potentially lethal genetic disease. CF manifestations are due to mutations in the CF transmembrane receptor transporter (CFTR) gene which codes for a protein (CFTR) that acts as an anion transporter, mainly chlorine, at epithelial cells where it is expressed. Cystic fibrosis related liver disease (CFRLD) includes a spectrum of hepatobiliary manifestations whose diagnosis and follow-up remains a challenge.

Cross-sectional, descriptive study from 10 Spanish cystic fibrosis units. Clinical and biochemical data obtained. Patients categorized into 3 groups according to liver involvement based on ESPGHAN 2017 criteria. Liver stiffness assessed by transient elastography (TE) and findings from abdominal ultrasound recorded. Statistics performed using SPSS v25.0.

We obtained hepatic TE data from 155 pediatric CF patients. Forty-four classified as CFRLD, 38 (86%) had CFRLD without cirrhosis and 6 (14%) had cirrhosis. Fourteen patients without CFRLD (12%) had ultrasound abnormalities. Mean liver elastography value (kPa) was 4.7 (3.5-5.3) in non-CFRLD and 6.09 (4.4-6.7) in CFRLD (p=0.01; T Student [T]).

CFRLD is common in children with CF. Transient elastography is a useful method for diagnosis and follow-up, as higher values of TE are found in patients with CFRLD.

Electrogenic transepithelial ion transport can be measured with the short-circuit current technique. Such experiments are frequently used to evaluate the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel that is defective in cystic fibrosis, one of the most frequent genetic diseases. Typically, CFTR activity is estimated from the effect of CFTRinh-172, a selective CFTR inhibitor. Unexpectedly, we found that CFTRinh-172, in addition to PPQ-102, another CFTR inhibitor, caused only partial inhibition of CFTR function, particularly in epithelia in pro-inflammatory conditions, which are characterized by abundant mucus secretion. We hypothesized that the mucus layer was responsible for the poor activity of CFTR inhibitors. Therefore, we treated the epithelial surface with the reducing agent dithiothreitol to remove mucus. Removal of mucus, confirmed by immunofluorescence, resulted in highly enhanced sensitivity of CFTR to pharmacological inhibition. Our results show that the mucus layer represents an important barrier whose presence limits the activity of pharmacological agents. This is particularly relevant for CFTR and the evaluation of therapeutic approaches for correction of the basic defect in cystic fibrosis. KEY POINTS: Activity of the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel can be evaluated by measuring the inhibition elicited by the selective blockers CFTRinh-172 and PPQ-102. In short-circuit current recordings on human airway epithelia, CFTR inhibitors had only a partial effect on cAMP-dependent chloride secretion, suggesting the possible contribution of other ion channels. The mucus layer covering the epithelial surface was removed with the reducing agent dithiothreitol. Treatment of epithelia with dithiothreitol markedly improved the efficacy of CFTR inhibitors. The partial effect of CFTR inhibitors might be explained by the presence of the mucus layer acting as a barrier.

With over 54,000 people affected, cystic fibrosis is one of the most common rare diseases in Europe. As life expectancy of this disease has steadily increased in recent years, the transition from pediatric to adult care has become a principal issue. This study aimed to identify facilitating and hindering factors in the transitional care of cystic fibrosis patients in order to derive indications for improving care.

A qualitative systematized review was conducted in May 2024 with a systematic search carried out in MEDLINE, CINAHL and Livivo, including European studies from 2009 to 2024. The studies' quality was assessed using the Critical Appraisal Skills Programme checklist for qualitative studies. Thematic analysis was applied for analyzing the data to identify categories.

Nine studies met the inclusion criteria. Their quality can be rated as medium to high. Parental support, commitment and social support were identified as beneficial factors. Preparation for the transition, appropriate communication and continuous follow-ups at the adult center also contributed to a continuous transition. However, the parents' changing roles, fears and the usual treatment in pediatrics were obstacles. The adjustment to the adult center and structural problems presented further barriers to transition.

Various factors were identified to influence the transition process in cystic fibrosis, with consistency across the studies. In practice, comprehensive care is required, focused on the patients' needs, with more information provided and enhanced collaboration among stakeholders. Further research regarding the long-term effects of transition and the utilization of structured transition programs is needed.

Cystic fibrosis (CF) is a chronic condition that requires complex and long-term treatments. While substantial research has explored treatment burden associated with CF; its impact remains complex to quantify. This review aims to identify the different methods used in the literature to measure treatment burden in people with CF (pwCF).

Five databases were searched for interventional and observational studies that focused primarily on treatment burden. The studies were presented using narrative synthesis structured around the perspective of treatment burden (subjective vs. objective).

This review synthesised 17 articles, which utilised subjective and objective measures separately or collectively. Twelve studies used subjective treatment burden measures (CF-specific and generic scales), while 14 studies used objective measures (treatment time, volume and complexity, and cost). Eight studies investigated treatment burden reported by proxy on behalf of children with CF. The most used measures were treatment time (9/17) and CF questionnaire-revised (CFQ-R) treatment burden subscale (6/17). Older age and lower lung function were associated with greater burden, treatment time, and complexity. Caregivers/parents reported worse treatment burden compared to children with CF (6-13 y/o) when completing the same measure.

No single measure used in the reviewed studies fully the multidimensional nature of treatment burden and summarised it in a single score. Given the rapidly evolving landscape of CF care a pragmatic approach to capture a broader array of treatment burden dimensions may be to routinely complement subjective measures with objective measures.

The leading cause of death for people with cystic fibrosis (pwCF) continues to be due to respiratory-related illnesses. Both wound repair and immune cell responses are dysregulated in the CF airways, creating a cycle of unresolved injury and perpetuating inflammation. PwCF are predisposed to colonization and infections with opportunistic bacteria like Pseudomonas aeruginosa (Pa), the most common adult pathogen in CF. Pa possesses key virulence factors that can exacerbate chronic inflammation and lung injury. With the approval of highly effective modulator therapies like elexacaftor/tezacaftor/ivacaftor (ETI), pwCF eligible for ETI have seen drastic improvements in lung function and clinical outcomes, including an increased life expectancy. While modulator therapies are improving bronchial epithelial cellular processes in wound repair and some areas of immunity, many of these processes do not reach a non-CF baseline state or have not been thoroughly studied. The effect of modulator therapy on Pa may lead to a reduction in infection, but in more longitudinal studies, there is not always eradication of Pa, and colonization and infection frequency can return to pre-modulator levels over time. Finally, in this review we explore the current state of additional treatments for CF lung disease, independent of CFTR genotype, including anti-inflammatories, phage-therapies, and Pa vaccines.

Cystic fibrosis (CF) is a genetic disease caused by dysfunction in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Patients with CF are hypersusceptible to Mycobacterium abscessus infection, a fast-growing mycobacterium and harmful opportunistic pathogen. Although CFTR dysfunction is known as a host susceptibility factor for M. abscessus infection, the functional impact of the trimeric Epithelial sodium Channel (ENaC), whose activity is negatively regulated by CFTR, towards M. abscessus infection has not been explored yet. To address this issue, we took advantage of miR-263a deficient Drosophila presenting a CF-like phenotype due to ENaC hyperactivity (ENaC+ ). We observed that the ENaC+ flies were as hypersusceptible to M. abscessus infection as the Cftr-deficient flies. The hypersensitivity of ENaC+ flies to M. abscessus infection was fully rescued by blocking ENaC hyperactivity, both chemically and genetically. Furthermore, we observed that ENaC hyperactivity per se was detrimental to ENaC+ Drosophila, as they were unable to mount an efficient humoral immune response. Upon infection, ENaC+ flies failed to upregulate 20-hydroxyecdysone production, which subsequently altered the production of protective antimicrobial peptides against M. abscessus. Overall, our results show that ENaC plays a key role in host susceptibility to M. abscessus infection and, correlatively to other CF pathogens.

Respiratory infections with multiresistant Pseudomonas aeruginosa are a major clinical problem, affecting mainly patients with pre-existing lung diseases such as cystic fibrosis (CF) or chronic obstructive pulmonary disease but also immunocompromised or elderly patients. We have previously shown that sphingosine, which is abundantly present on epithelial cells of the respiratory tract in healthy humans and wild-type mice, but almost undetectable on the surface of epithelial cells of the respiratory tract from CF patients and CF mice, efficiently kills many bacterial species in vitro and in vivo. Here, we show that sphingosine very rapidly induces marked changes in the membrane of P. aeruginosa with a rolling of the membrane followed by destruction of the bacteria. Sphingosine induced a degradation of cardiolipin via the maintenance of lipid asymmetry (Mla) system in P. aeruginosa. Degradation of cardiolipin induced by sphingosine is prevented in P. aeruginosa mutants of MlaY and reduced in mutants of MlaZ and MlaA. Mutants of MlaY and MlaZ were resistant to sphingosine-induced death of P. aeruginosa. In summary, our data indicate that sphingosine induces the death of P. aeruginosa by a persisting degradation of cardiolipin by the Mla system leading to severe membrane changes in bacteria, while leaving mammalian cells, devoid of cardiolipin in their plasma membrane, alive.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has significantly changed the course of the disease in people with cystic fibrosis (CF) (pwCF). The approved triple therapy of elexacaftor, tezacaftor and ivacaftor (ETI), commercially known as Trikafta, increases CFTR channel function, leading to improvements in sweat chloride concentration, exercise capacity, body mass index, lung function and chronic respiratory symptoms. Because of this, the majority of pwCF are living longer and having fewer CF exacerbations. However, colonization with the common CF respiratory pathogens persists and remains a major cause of morbidity and mortality. Here, we review the current literature on the effect of ETI on the respiratory microbiota and discuss the challenges in addressing CF lung infections in the era of these new life-extending therapies.

Cystic fibrosis-related liver disease (CFRLD) is a health problem that can affect as many as 30-40% of cystic fibrosis patients by the age of 12 years. We studied the epidemiology of CFRLD thanks to the first exclusively pediatric CFRLD patient registry to date.

Descriptive cross-sectional study. Information from medical records from January 2018 to December 2020 is collected. CFRLD was classified according to the European Society of Paediatric Gastroenterology, Hepatology and Nutrition 2017 criteria.

Data were collected from 168 pediatric patients diagnosed with CFRLD (90.5% liver involvement without cirrhosis and 8.5% multinodular cirrhosis).

In this national registry, including exclusively pediatric population, liver disease is diagnosed around 7 years of age. Liver involvement without cirrhosis is the most frequent finding among our patients but about 9% of the patients already had cirrhosis. CFRLD is one of the challenges faced by pediatric gastroenterologists in the future and national registries give us the opportunity to further study and broaden our knowledge.

Cystic fibrosis (CF) is a disease with a broad clinical and genetic spectrum of manifestations, significantly impacting the quality and duration of life of patients. At present, a diagnosis of CF enables the disease to be identified at the earliest stages of its development. The accelerated advancement of scientific knowledge and contemporary research techniques has transformed the methodology employed in the treatment of CF, encompassing a spectrum of approaches from symptomatic management to pathogenetic therapies. Pathogenetic therapy represents an approach to treatment that aims to identify methods of restoring the function of the CFTR gene. The objective of this review was to analyse and summarize the available scientific data on the pathogenetic therapy of CF. This paper considers various approaches to the pathogenetic therapy of CF that are based on the use of targeted drugs known as CFTR modulators. The article presents studies employing gene therapy techniques for CF, which are based on the targeted delivery of a normal copy of the CFTR gene cDNA to the respiratory tract via viral or non-viral vectors. Some studies have demonstrated the efficacy of RNA therapeutic interventions in restoring splicing, promoting the production of mature RNA, and increasing the functional expression of the CFTR protein. The review also analyzes literature data that consider methods of etiotropic therapy for CF, which consists of targeted correction of the CFTR gene using artificial restriction enzymes, the CRISPR/Cas9 system and a complex of peptide-nucleic acids. In a prospective plan, the use of cell therapy methods in the treatment of lung damage in CF is considered.

The increasing life expectancy of people with cystic fibrosis (pwCF), largely driven by advancements in early diagnosis, multidisciplinary care and the recent introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, is likely to herald a shift in the focus of care toward managing the complexities of ageing. This review highlights key challenges and research priorities for addressing the health needs of an ageing CF population. A growing body of evidence underscores the heightened risks of cancers, cardiovascular diseases and changing nutritional and metabolic profiles as pwCF age. CFTR modulators have improved clinical outcomes, but their effects on inflammation, immunity and long-term disease trajectories remain incompletely understood. Nutritional management, particularly the implications of obesity and body composition, poses new challenges, as does the potential accelerated ageing of immune and pulmonary systems in CF. Emerging issues such as menopause in females with CF, lifetime antimicrobial resistance and the interplay between chronic inflammation and ageing further complicate the care landscape. The review emphasises the urgent need for multidisciplinary research programmes that integrate clinical, patient and community perspectives. Leveraging established CF registries, clinical trial networks and collaborations with ageing research frameworks is critical to addressing these challenges. Ultimately, the goal is to ensure that pwCF not only live longer but also experience improved quality of life and holistic wellbeing as they realise the full benefits of therapeutic advances.

Medication adherence data are an important quality indicator in cystic fibrosis (CF) care, yet real-time objective data are not routinely available. An online application (CFHealthHub) has been designed to deliver these data to people with CF and their clinical team. Adoption of this innovation is the focus of an National Health Service England-funded learning health system and Quality Improvement Collaborative (QIC). This study applies the capability, opportunity, and motivation model of behavior change to assess whether the QIC had supported healthcare professionals' uptake of accessing patient adherence data.

This was a mixed-method study, treating each multidisciplinary team as an individual case. Click analytic data from CFHealthHub were collected between January 1, 2018, and September 22, 2019. Thirteen healthcare practitioners participated in semi-structured interviews, before and after establishing the QIC. Qualitative data were analyzed using the behavior change model.

The cases showed varied improvement trajectories. While two cases reported reduced barriers, one faced persistent challenges. Participation in the QIC led to enhanced confidence in the platform's utility. Reduced capability, opportunity, and motivation barriers correlated with increased uptake, demonstrating value in integrating behavior change theory into QICs.

QICs can successfully reduce barriers and enable uptake of e-health innovations such as adherence monitoring technology. However, ongoing multi-level strategies are needed to embed changes. Further research should explore sustainability mechanisms and their impact on patient outcomes.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity response to the allergens of Aspergillus fumigatus, which is the most frequently isolated fungus from the sputum of cystic fibrosis (CF) patients. Because a low number of Th17 lymphocytes is associated with the risk of fungal infections, we investigated inflammatory markers, Th17 cells, and T-cell polarization in CF patients with ABPA.

We analyzed the levels of inflammatory markers, blood counts, chemokines, cytokines, and T cell subsets in blood and sputum of CF subjects to elucidate the immunological factors associated with CF patients with Aspergillus fumigatus (AF) positive sputum (AFS+) or with ABPA.

We observed that AFS+ patients have higher sputum and blood IL-6 levels than AF-negative sputum (AFS-) patients. Analysis of blood memory T-helper subsets associated with Th1, Th2, and Th17 polarization among circulating CD45RA-/CD4+ memory T-cell subsets showed higher numbers of CCR4+/CCR6+/CXCR3- and CCR4+/CCR6+/CXCR3+ memory CD4 cells in AFS+ compared to AFS- subjects. Further analysis of Th17-related subsets and IL-17 secreting T cells in subjects with AFS+ showed that those with ABPA have statistically significantly lower levels of Th17 cells as compared to those without ABPA.

In CF, AF airway colonization is associated with increased blood counts of Th17-related subsets. However, CF patients with ABPA exhibit lower numbers of CCR4+/CCR6+/CXCR3+ memory CD4 cells and IL-17-secreting CD4 cells compared to control subjects and CF patients without AF sensitization.

This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

Drug-device combinations (DDCs) are therapeutic products that integrate drugs with medical devices to enhance treatment efficacy and/or safety. These combinations hold significant promise for rare diseases, which affect millions of patients globally, by improving drug delivery, targeting specific organs, and reducing side effects. However, the regulatory framework for DDCs remains complex and lacks specific incentives for rare diseases, unlike orphan drugs. This review examines regulatory approaches and case studies of DDCs in rare diseases, and highlights specific challenges and untapped opportunities. Moreover, the publication discusses recommendations to overcome these challenges through tailored policies and incentives to unlock the potential of DDCs in the context of rare diseases.

Cystic Fibrosis (CF) is a life-limiting, inherited condition in which a novel class of oral medicine, CFTR modulators, has revolutionised symptoms and health indicators, providing an opportunity to evaluate traditional treatment regimens with the hope of reducing burden. Additionally, there is cautious optimism that life expectancy for people with CF born today could ultimately compare to that of the general population. Given this potential, there is a need and requirement to optimise treatment to balance burden with the best clinical outcomes for each person with CF in an individualised manner. Personalised data-Linkage to Understand Treatment Optimisation (PLUTO) is a clinical framework, developed within the 14-Centre UK CFHealthHub Learning Health System collaborative, designed for use at an individual level for people with CF taking CFTR modulators. The PLUTO framework encourages use of two routinely collected clinical outcome measure (FEV1 and BMI) to determine health status. Where FEV1 or BMI trends suggest that optimal health outcomes are not being achieved for a person with CF, PLUTO supports consideration of adherence to both CFTR modulators and inhaled therapy to help guide the next steps. PLUTO is designed to support people with CF and their clinical teams to individualise care and optimise outcomes for those taking CFTR modulators, using data available in routine clinical encounters.

CRISPR-Cas9 technology has revolutionized genetic engineering, offering precise and efficient genome editing capabilities. This review explores the application of CRISPR-Cas9 for cystic fibrosis (CF), particularly targeting mutations in the CFTR gene. CF is a multiorgan disease primarily affecting the lungs, gastrointestinal system (e.g., CF-related diabetes (CFRD), CF-associated liver disease (CFLD)), bones (CF-bone disease), and the reproductive system. CF, a genetic disorder characterized by defective ion transport leading to thick mucus accumulation, is often caused by mutations like ΔF508 in the CFTR gene. This review employs a systematic methodology, incorporating an extensive literature search across multiple academic databases, including PubMed, Web of Science, and ScienceDirect, to identify 40 high-quality studies focused on CRISPR-Cas9 applications for CFTR gene editing. The data collection process involved predefined inclusion criteria targeting experimental approaches, gene-editing outcomes, delivery methods, and verification techniques. Data analysis synthesized findings on editing efficiency, off-target effects, and delivery system optimization to present a comprehensive overview of the field. The review highlights the historical development of CRISPR-Cas9, its mechanism, and its transformative role in genetic engineering and medicine. A detailed examination of CRISPR-Cas9's application in CFTR gene correction emphasizes the potential for therapeutic interventions while addressing challenges such as off-target effects, delivery efficiency, and ethical considerations. Future directions include optimizing delivery systems, integrating advanced editing tools like prime and base editing, and expanding personalized medicine approaches to improve treatment outcomes. By systematically analyzing the current landscape, this review provides a foundation for advancing CRISPR-Cas9 technologies for cystic fibrosis treatment and related disorders.

Established morpho-functional chest magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion in people with cystic fibrosis (pwCF) using a dedicated scoring system. Functional assessment is performed using contrast-enhanced (CE) perfusion MRI. Novel matrix pencil decomposition MRI (MP-MRI) is a contrast agent-free alternative, but further validation of this technique is needed.

The aim of this study was to evaluate the applicability of the validated morpho-functional chest MRI score for CE perfusion and MP perfusion MRI in a multireader approach.

Twenty-seven pwCF (mean age 20.8 years, range 8.4-45.7 years) underwent morpho-functional MRI including CE perfusion and MP perfusion MRI in the same examination. Nine blinded chest radiologists of different experience levels assessed lung perfusion and applied the validated chest MRI score to CE- and MP-MRI. Inter-reader agreement of perfusion scores in CE- and MP-MRI were compared with each other and with the MRI morphology score. Differences according to the readers' experience were also analyzed.

The CE perfusion scores were overall lower than the MP perfusion scores (6.2 ± 3.3 vs. 6.9 ± 2.0; p < 0.05) with a strong correlation between both perfusion scores (r = 0.74; p < 0.01). The intraclass correlation coefficient (ICC) as measure for inter-reader agreement was good and significant for both perfusion scores, but higher for the CE perfusion score (0.75, p < 0.001) than for MP perfusion scores (0.61, p < 0.001). The Bland-Altman analysis revealed a difference in CE and MP perfusion scores with more extreme values in CE perfusion scores compared to MP perfusion scores (r = 0.62, p < 0.001). The morphology score showed a moderate to good correlation with the CE perfusion score (r = 0.73, p < 0.01) and the MP perfusion score (r = 0.55, p < 0.01). We did not find a difference in scoring according to the radiological experience level.

The established chest MRI score can be applied both to validated CE and novel MP perfusion MRI with a good interreader reliability. The remaining difference between CE and MP-MRI scores may be explained by a lack of routine in visual analysis of MP-MRI and may favor an automated analysis for use of MP-MRI as a noninvasive outcome measure.

Cystic fibrosis (CF) is a rare disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a chloride channel with an important role in the airways. Despite the clinical efficacy of present modulators in restoring the activity of defective CFTR, there are patients who show persistent pulmonary infections, mainly due to Pseudomonas aeruginosa. Recently, we reported an unprecedented property of antimicrobial peptides i.e. Esc peptides, which consists in their ability to act as potentiators of CFTR carrying the most common mutation (the loss of phenylalanine 508) affecting protein folding, trafficking and gating. In this work, by electrophysiology experiments and computational studies, the capability of these peptides and de-novo designed analogs was demonstrated to recover the function of other mutated forms of CFTR which severely affect the channel gating (G551D and G1349D). This is presumably due to direct interaction of the peptides with the nucleotide binding domains (NBDs) of CFTR, followed by a novel local phenomenon consisting in distancing residues located at the cytosolic side of the NBDs interface, thus stabilizing the open conformation of the pore at its cytosolic end. The most promising peptides for the dual antimicrobial and CFTR potentiator activities were also shown to display antipseudomonal activity in conditions mimicking the CF pulmonary ion transport and mucus obstruction, with a higher efficacy than the clinically used colistin. These studies should assist in development of novel drugs for lung pathology in CF, with dual CFTR potentiator and large spectrum antibiotic activities.