Cystic Fibrosis Therapy Research Articles

The Future of Cystic Fibrosis Care: Exploring AI's Impact on Detection and Therapy

: Cystic Fibrosis (CF) is a fatal hereditary condition marked by thicker mucus production, which can cause problems with the digestive and respiratory systems. The quality of life and survival rates of CF patients can be improved by early identification and individualized therapy measures. With an emphasis on its applications in diagnosis and therapy, this paper investigates how Artificial Intelligence (AI) is transforming the management of Cystic Fibrosis (CF). AI-powered algorithms are revolutionizing CF diagnosis by utilizing huge genetic, clinical, and imaging data databases. In order to identify CF mutations quickly and precisely, machine learning methods evaluate genomic profiles. Furthermore, AI-driven imaging analysis helps to identify lung and gastrointestinal issues linked to cystic fibrosis early and allows for prompt treatment. Additionally, AI aids in individualized CF therapy by anticipating how patients will react to already available medications and enabling customized treatment regimens. Drug repurposing algorithms find prospective candidates from already-approved drugs, advancing treatment choices. Additionally, AI supports the optimization of pharmacological combinations, enhancing therapeutic results while minimizing side effects. AI also helps with patient stratification by connecting people with CF mutations to therapies that are best for their genetic profiles. Improved treatment effectiveness is promised by this tailored strategy. The transformational potential of artificial intelligence (AI) in the field of cystic fibrosis is highlighted in this review, from early identification to individualized medication, bringing hope for better patient outcomes, and eventually prolonging the lives of people with this difficult ailment.

Effectiveness of hypertonic saline with or without hyaluronic acid among patients with cystic fibrosis: a systematic review and meta-analysis

Background: The clinical effectiveness of hypertonic saline (HS) in individuals with cystic fibrosis (CF) can be compromised by adverse effects. The objective of this study was to examine the efficacy of hyaluronic acid (HA) in mitigating these negative occurrences. Methods: A comprehensive review of the literature was carried out using three electronic databases: Medline, Cochrane Central, and Embase. This systematic review and meta-analysis investigate the efficacy of hypertonic saline (HS) with and without hyaluronic acid (HA) in treating cystic fibrosis. Primary outcomes include the incidence of cough, throat irritation, unpleasant taste, and changes in FEV1. Our findings suggest that adding HA to HS significantly reduces adverse effects and enhances patient tolerability, marking a potential improvement in cystic fibrosis therapy. Risk ratios (RRs) and mean differences (MDs) with 95% CI were used to present evaluations. The quality of RCTs was evaluated using the Cochrane Risk of Bias Tool (CRBT). The quality of the observational study was evaluated using the Newcastle–Ottawa Scale. Results: From the 1960 articles retrieved from the initial search, five relevant studies (n=236 patients) were included in the final analysis. Compared with patients only on HS, patients with HS and HA were significantly less likely to experience cough (RR: 0.45; 95% CI, 0.28–0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22–0.81, P=0.009), and unpleasant smell (RR: 0.43; 95% CI, 0.23–0.80, P=0.09). In addition, patients with HS with HA had significantly less forced expiratory volume (FEV1) (MD: −2.97; 95% CI, −3.79–−2.15, P=0.52), compared to patients only on HS. Patients on HA + HS had significantly lower rates of cough (RR: 0.45; 95% CI, 0.28–0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22–0.81, P=0.009), and bad smell (RR: 0.43; 95% CI, 0.23–0.80, P=0.09) when compared to patients on HS alone. Furthermore, compared to patients solely on HS, patients with HS plus HA exhibited a substantially lower forced expiratory volume (FEV1) (MD: −2.97; 95% CI, −3.79 to −2.15, P=0.52) as well. Conclusion: For CF patients who need ongoing HS therapy and have a history of poor therapy tolerance, adding HA is beneficial.

Гено-фенотипические особенности муковисцидоза у российских детей из Чеченской и Карачаево-Черкесской Республик

Background: Cystic fibrosis (CF) is an autosomal recessive disease that occurs with a frequency of 1:1,500 to 1:5,000 newborns, according to the World Health Organization. In the Russian Federation, the average incidence of the disease is 1:10,000 newborns. The medical and social significance of this disease is associated with the early disability of patients, the need for long-term treatment and constant follow-up, as well as the heterogeneity of phenotypic manifestations, which in turn requires early diagnosis using molecular genetic methods. The aim of the study: To study the clinical and molecular genetic characteristics of children with CF from the Chechen and Karachay-Cherkess Republics. Materials and methods: The study included 237 patients with a confirmed diagnosis of CF. Molecular genetic diagnostics was performed using the method of mass parallel sequencing using a hybridization target panel that includes the entire CFTR gene. Sequencing was performed on the MiSeq platform. All causal nucleotide variants were validated using Sanger sequencing. Results: The most common amino acid variants of the CFTR gene in patients with CF from the Chechen Republic are: p.Y515* (94 alleles/78.3%), p.E92K (18 alleles/15%). The presence of variants p.Y515* and p.E92K in the heterozygous state in the genotype is more often a favorable prognostic factor for the absence of pancreatic lesion. The main distinctive clinical feature of these patients is the onset of the disease with manifestations of pseudo-Bartter syndrome. The major amino acid variant of the CFTR gene in patients with CF from the Karachay-Cherkess Republic is: p.W1282* (28 alleles/70%). The number of patients with pseudo-Bartter syndrome was 54.5%. In 90% of cases, in patients who are homo- and heterozygous according to p.W1282*, a severe degree of pancreatic insufficiency was noted. Conclusion: Patients with cystic fibrosis from the Chechen and Karachay-Cherkess Republics are a difficult category of patients, despite neonatal screening, and cystic fibrosis therapy developed and implemented. This is partly due to the peculiarities of the phenotype and the unique distribution of alleles and genotypes of the CFTR gene. The high number of homozygous variants of the CFTR gene in patients from the Chechen and Karachay-Cherkess Republics is probably due to monoethnic marital assortativity.

Effect of CFTR Modulators on Oxidative Stress and Autophagy in Non-CFTR-Expressing Cells.

The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the individual components and ETI may have potential off-target effects, highlighting the need to understand how these modulators impact cellular physiology, particularly in cells that do not express CF transmembrane conductance regulator (CFTR). We used HEK293 cells, as a cell model not expressing the CFTR protein, to evaluate the effect of ETI and each of its components on autophagic machinery and on the Rab5/7 components of the Rab pathway. We firstly demonstrate that the single modulators Teza and Iva, and the combinations ET and ETI, increased ROS production in the absence of their target while decreasing it in cells expressing the CFTR ∆F508del. This increase in cellular stress was followed by an increase in the total level of polyubiquitinated proteins as well as the p62 level and LC3II/LC3I ratio. Furthermore, we found that ETI had the opposite effect on Rabs by increasing Rab5 levels while decreasing Rab7. Interestingly, these changes were abolished by the expression of mutated CFTR. Overall, our data suggest that in the absence of their target, both the individual modulators and ETI increased ROS production and halted both autophagic flux and plasma membrane protein recycling.

Same-Day Repeatability and 28-Day Reproducibility of Xenon MRI Ventilation in Children With Cystic Fibrosis in a Multi-Site Trial.

MRI with xenon-129 gas (Xe MRI) can assess airflow obstruction and heterogeneity in lung diseases. Specifically, Xe MRI may represent a sensitive modality for future therapeutic trials of cystic fibrosis (CF) therapies. The reproducibility of Xe MRI has not yet been assessed in the context of a multi-site study. To determine the same-day repeatability and 28-day reproducibility of Xe MRI in children with CF. Four-center prospective, longitudinal. Thirty-eight children (18 females, 47%), median interquartile range (IQR) age 12 (9-14) years old, with mild CF (forced expiratory volume in 1 second (FEV1) ≥85% predicted). 3-T, two-dimensional (2D) gradient-echo (GRE) sequence. Xe MRI, FEV1, and nitrogen multiple-breath wash-out for lung-clearance index (LCI2.5) were performed. To assess same-day reproducibility, Xe MRI was performed twice within the first visit, and procedures were repeated at 28 days. Xe hypoventilation was quantified using ventilation-defect percentage (VDP) and reader-defect volume (RDV). For VDP, hypoventilated voxels from segmented images were identified using a threshold of <60% mean whole-lung signal and expressed as a percentage of the lung volume. For RDV, hypoventilation was identified by two trained readers and expressed as a percentage. Inter-site comparisons were conducted using Kruskal-Wallis nonparametric tests with Dunn's multiple-comparisons tests. Differences for individuals were assessed using Wilcoxon matched-pairs tests. Bland-Altman tests were used to evaluate same-day repeatability, 28-day reproducibility, and inter-reader agreement. A P-value ≤0.05 was considered significant. Median FEV1 %-predicted was 96.8% (86%-106%), and median LCI2.5 was 6.6 (6.3-7.4). Xe MRI had high same-day reproducibility (mean VDP difference 0.12%, 95% limits of agreement [-3.2, 3.4]; mean RDV difference 0.42% [-2.5, 3.3]). At 28 days, 26/31 participants (84%) fell within the same-day 95% limits of agreement. Xe MRI may offer excellent same-day and short-term reproducibility. 2 TECHNICAL EFFICACY: Stage 2.

Lung transplant referral considerations for individuals with cystic fibrosis.

The cystic fibrosis (CF) Foundation issued guidelines to promote timely lung transplant referral for people with cystic fibrosis (pwCF) in 2019. Since then more has been published to help refine this complex decision. The goal of this review is to summarize the recent literature informing disease severity in CF, barriers to referral for pwCF and guide timely and appropriate lung transplant referrals. Existing guidelines utilize the degree of airflow limitation as the primary criteria to refer for lung transplant, yet this variable has some prognostic uncertainty. Novel prognostic tools may provide more reliable metrics for predicting who with CF is at greatest risk of dying from their lung disease and could be used as an indicator for when to refer. In addition, updated analyses of national registry data have highlighted the significance of hemoptysis, low body mass index, and extra-pulmonary organ failure, as important prognostic markers. PwCF with these complications have historically been under-referred for lung transplant despite data suggesting lung transplant can be safe for some in these populations. Early referral should be considered in the presence of these complications. This review builds on existing guidelines by incorporating novel data to better determine when lung transplant referral is most appropriate. Improved prognostic tools are still needed to decrease the chances of pwCF dying without consideration of lung transplant. It is still unclear how novel therapies for CF may change the need and timing for lung transplant referral.

Phage Therapy: An Alternative Approach to Combating Multidrug-Resistant Bacterial Infections in Cystic Fibrosis.

Patients with cystic fibrosis (CF) are prone to developing life-threatening lung infections with a variety of pathogens that are difficult to eradicate, such as Burkholderia cepacia complex (Bcc), Hemophilus influenzae, Mycobacterium abscessus (Mab), Pseudomonas aeruginosa, and Staphylococcus aureus. These infections still remain an important issue, despite the therapy for CF having considerably improved in recent years. Moreover, prolonged exposure to antibiotics in combination favors the development and spread of multi-resistant bacteria; thus, the development of alternative strategies is crucial to counter antimicrobial resistance. In this context, phage therapy, i.e., the use of phages, viruses that specifically infect bacteria, has become a promising strategy. In this review, we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.

Cystic fibrosis year in review 2023.

This past year, there were many important advances for patients with cystic fibrosis (CF). Of the many publications related to CF in 2023, there was further evaluation of highly effective modulator therapy, new assessments and guidelines for clinical manifestations and therapies for CF, advances in newborn screening and diagnosis, and evaluation of outcomes for people with CF transmembrane conductance regulator-related metabolic syndrome/CF screen positive, inconclusive diagnosis. The aim of this review article is not to provide a full assessment of the wide range of articles published in 2023, but to provide a brief review of publication that may lead to changes in clinical care.

Development of a Clonal and High-Yield Mammalian Cell Line for the Manufacturing of a Hyperactive Human DNase I with Extended Plasma Half-Life Using PASylation® Technology.

Cumulative evidence from several pre-clinical studies suggests that restoration of plasma DNase activity in a thrombo-inflammatory state may improve clinical outcomes. Following injury, hyperactivated immune cells release large amounts of granular proteins together with DNA, which often accumulate in the surrounding environment in so-called neutrophil extracellular traps (NETs). Degradation of excess NETs by systemic DNase administration offers a promising therapeutic approach to ameliorate inflammation and dissolve intravascular clots. In order to expand the therapeutic utility of human DNase I, a variant of the enzyme was developed that has both a prolonged systemic half-life and a higher catalytic activity compared to Dornase alfa (Pulmozyme®), the recombinant form of DNase I approved for inhaled therapy of cystic fibrosis. The hyperactive enzyme was "PASylated" by genetic fusion with a strongly hydrophilic and biodegradable PAS-polypeptide to increase its hydrodynamic volume and retard kidney filtration. A stable TurboCell™ CHO-K1-based cell line was generated which is suitable for the future production of PASylated DNase I according to good manufacturing practice (GMP). Furthermore, a robust bioprocess strategy was devised and an effective downstream process was developed. The final protein product is characterized by excellent purity, favorable physicochemical properties, a 14-fold higher DNA-degrading activity than Dornase alfa and a sustained pharmacokinetic profile, with a 22-fold slower clearance in rats.

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies.

A common life-threatening hereditary disease, Cystic Fibrosis (CF), affects primarily Caucasian infants. High sweat-salt levels are observed as a result of a single autosomal mutation in chromosome 7 that affects the critical function of the cystic fibrosis transmembrane regulator (CFTR). For establishing tailored treatment strategies, it is important to understand the broad range of CFTR mutations and their impacts on disease pathophysiology. This study thoroughly investigates the six main classes of classification of CFTR mutations based on their functional effects. Each class is distinguished by distinct molecular flaws, such as poor protein synthesis, misfolding, gating defects, conduction defects, and decreased CFTR expression at the apical membrane. Furthermore, this paper focuses on the emerging field of CFTR modulators, which intend to restore CFTR function or mitigate its consequences. These modulators, which are characterized by the mode of action and targeted mutation class, have the potential to provide personalized therapy regimens in CF patients. This review provides valuable insights into the genetic basis of CF pathology, and highlights the potential for precision medicine methods in CF therapy by thoroughly investigating CFTR mutation classification and related modulators.

МОРФОЛОГИЧЕСКИЕ ИЗМЕНЕНИЯ В ПЕЧЕНИ ПРИ МУКОВИСЦИДОЗЕ У ДЕТЕЙ

Background. Cystic fibrosis (CF) is an autosomal recessive disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, characterized by damage to vital organs, a severe course and an unfavorable outcome. Liver cirrhosis is a relatively rare manifestation of cystic fibrosis. Objective. To study the causes of death, hepatic morphological changes in CF according to autopsy data and to present a description of a case of CF with rapidly progressing liver cirrhosis in a 6-year-old child. Material and methods. An analysis of clinical, laboratory and instrumental studies of CF and the results of hepatic morphological changes was carried out according to the data of 10 autopsies performed at the State Healthcare Institution "GRCPB". Results. Among the 10 patients died from a mixed form of CF, there were 5 patients aged 1-3 months, 2 patients aged 1.5 years, 1 patient aged 4.5 years, 1 patient aged 6 years and 1 patient was 19 years old. Infant patients had predominant intestinal damage with the development of intestinal obstruction and peritonitis, older age groups had lung damage with the development of chronic pulmonary heart disease, chronic pulmonary heart failure, and to a lesser extent - pathology of the pancreas and gastrointestinal tract. In one 6-year-old patient, CF was complicated by diabetes mellitus as well as liver cirrhosis with portal hypertension. All patients had severe protein-energy deficiency, psychosomatic and psychopathological symptoms. The results of pathohistological examination of the liver of infant patients showed dilation of the interlobular bile ducts with cholestasis and periductal fibrosis. The severity of these liver changes increased gradually alongside with patients’ age, including the progression of fatty degeneration. In a number of cases, diffuse fibrosis was recorded, resulting in liver cirrhosis with portal hypertension. At autopsy, the extrahepatic bile ducts and gallbladder were dilated and filled with bile of a viscous consistency. Conclusions. The nature of hepatic morphological changes in CF depends on the age of the patients and on the influence of exogenous factors. Only timely diagnosis and early complex therapy for CF will reduce the progression of irreversible processes in various organs and prolong the life of patients.

P316 Increasing numbers of pregnancies due to modulator therapy in cystic fibrosis

P316 Increasing numbers of pregnancies due to modulator therapy in cystic fibrosis

WS02.06 Impact of elexacaftor/tezacaftor/ivacaftor on utilisation of maintenance therapies in cystic fibrosis: Danish nationwide register study

WS02.06 Impact of elexacaftor/tezacaftor/ivacaftor on utilisation of maintenance therapies in cystic fibrosis: Danish nationwide register study

P024 Analysis of the effect of cytochrome P450 genes polymorphism on the efficacy and safety of CFTR modulator therapy in cystic fibrosis

P024 Analysis of the effect of cytochrome P450 genes polymorphism on the efficacy and safety of CFTR modulator therapy in cystic fibrosis

EPS9.08 A modelling framework for epithelial airway fluid and ion transport with multiple cell types: implications for success or failure in gene therapies for cystic fibrosis

EPS9.08 A modelling framework for epithelial airway fluid and ion transport with multiple cell types: implications for success or failure in gene therapies for cystic fibrosis

Bronchoscopy-guided antimicrobial therapy for cystic fibrosis.

Bronchoscopy-guided antimicrobial therapy for cystic fibrosis.

Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis.

The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

340 Anti-CD20 attenuates lung humoral and cellular immune responses: implications for gene therapy in Cystic Fibrosis

OBJECTIVES/GOALS: Re-administration of inhaled gene therapies has the potential to overcome low correction efficiencies and limiting immune responses observed in previous trials of gene therapy for Cystic Fibrosis. We therefore tested the hypothesis that pre-treatment with a B-cell depleting α ± CD20 antibody would permit vector re-administration. METHODS/STUDY POPULATION: We first selected Adenoviral (Ad) vectors to study initially due to their well-known ability to elicit potent immune responses. Mice were dosed with a depleting α ± CD20 antibody or isotype control 2 days prior to delivery of Ad-Luc. 4 weeks later, mice were euthanized to assess the development of anti-vector immune responses. Flow cytometry and single-cell RNA sequencing were used to evaluate the development of lung-resident memory cells. Serum and airway antibody responses were assessed by ELISA. After 4 weeks, mice were dosed with Ad-LacZ and euthanized 3 days later to assess efficiency of second-round gene transfer by β-galactosidase activity assay. Similar methods were used in a pilot experiment with Adeno-associated virus vector (AAV), but with euthanasia 3 weeks after secondary gene transfer. RESULTS/ANTICIPATED RESULTS: Delivery of Ad vectors leads to the development of lung-resident memory B and T-cells. The depletion of B-cells prior to first-round vector delivery attenuated airway T-cell infiltration and serum IgG production, abrogated mucosal IgG and IgA production, and completely rescued secondary gene transfer. Genetically modified mouse models suggest secreted antibodies are critical in prevention of vector redosing. AAV vectors were found to be less immunogenic than Ad vectors, with only partial reduction of second-round gene transfer. However, anti-CD20 provided no benefit for AAV redelivery. DISCUSSION/SIGNIFICANCE: Mucosal humoral immunity is critical in preventing re-administration of Adenoviral vectors. Impairment of B-cell responses by α ± CD20 treatment prior to vector delivery allows re-administration and may help overcome low efficiencies of CF gene therapy. AAV vectors may be less susceptible to neutralization by pre-existing immunity.

Enzyme-Linked Lipid Nanocarriers for Coping Pseudomonal Pulmonary Infection. Would Nanocarriers Complement Biofilm Disruption or Pave Its Road?

Cystic fibrosis (CF) is associated with pulmonary Pseudomonas aeruginosa infections persistent to antibiotics. To eradicate pseudomonal biofilms, solid lipid nanoparticles (SLNs) loaded with quorum-sensing-inhibitor (QSI, disrupting bacterial crosstalk), coated with chitosan (CS, improving internalization) and immobilized with alginate lyase (AL, destroying alginate biofilms) were developed. SLNs (140-205 nm) showed prolonged release of QSI with no sign of acute toxicity to A549 and Calu-3 cells. The CS coating improved uptake, whereas immobilized-AL ensured >1.5-fold higher uptake and doubled SLN diffusion across the artificial biofilm sputum model. Respirable microparticles comprising SLNs in carbohydrate matrix elicited aerodynamic diameters MMAD (3.54, 2.48 µm) and fine-particle-fraction FPF (65, 48%) for anionic and cationic SLNs, respectively. The antimicrobial and/or antibiofilm activity of SLNs was explored in Pseudomonas aeruginosa reference mucoid/nonmucoid strains as well as clinical isolates. The full growth inhibition of planktonic bacteria was dependent on SLN type, concentration, growth medium, and strain. OD measurements and live/dead staining proved that anionic SLNs efficiently ceased biofilm formation and eradicated established biofilms, whereas cationic SLNs unexpectedly promoted biofilm progression. AL immobilization increased biofilm vulnerability; instead, CS coating increased biofilm formation confirmed by 3D-time lapse confocal imaging. Incubation of SLNs with mature biofilms of P. aeruginosa isolates increased biofilm density by an average of 1.5-fold. CLSM further confirmed the binding and uptake of the labeled SLNs in P. aeruginosa biofilms. Considerable uptake of CS-coated SLNs in non-mucoid strains could be observed presumably due to interaction of chitosan with LPS glycolipids in the outer cell membrane of P. aeruginosa. The biofilm-destructive potential of QSI/SLNs/AL inhalation is promising for site-specific biofilm-targeted interventional CF therapy. Nevertheless, the intrinsic/extrinsic fundamentals of nanocarrier-biofilm interactions require further investigation.

Pancreatitis in cystic fibrosis: Presentation, medical and surgical management, and the impact of modulator therapies.

Patients with Cystic Fibrosis (CF) are at increased risk of acute (AP) and chronic (CP) pancreatitis, and their complications. The extent of remaining healthy pancreatic parenchyma determines the risk of developing future episodes of pancreatitis, as well as pancreatic exocrine or endocrine insufficiency. Pancreatitis may be the presenting symptom of CF, and genetic testing is especially important in pediatrics. AP and recurrent AP are managed with intravenous fluid hydration and pain control, in addition to early refeeding and treatment of complications. With the use of modulator therapy in CF, pancreatic function may be restored to some extent. CP related pain is managed with analgesics and neuromodulators, with surgery if indicated in specific situations including TPIAT as a possible type of surgical intervention. Long-term sequelae of CP in patients with CF include exocrine pancreatic insufficiency treated with pancreatic enzyme replacement therapy, fat-soluble vitamin deficiencies and associated metabolic complications such as bone disease/osteoporosis, pancreatogenic diabetes, and less commonly, pancreatic cancer. We review the presentation and etiologies of pancreatitis in CF patients as well as the management of AP and CP primarily in children.