Development and validation of a novel personalized electronic patient-reported outcome measure to assess quality of life (Q-LIFE): a prospective observational study in people with Cystic Fibrosis.

Background: Generic and disease-specific patient-reported outcome measures (PROMs) may lack relevance and sensitivity on a patient-level in chronic diseases with differential disease expression and high individual variability, such as Cystic Fibrosis (CF). This study aimed to develop and validate a novel personalized electronic PROM (ePROM) that captures relevant aspects of quality of life in individuals with CF. Methods: The Q-Life app was developed as a short personalized ePROM to assess individual quality of life. Psychometric properties were assessed in a single-center cross-sectional study between September 2019 and September 2021 and in a prospective cohort study between September 2021 and September 2022. Findings: Combined studies included 223 participants (median age: 24 years, IQR: 19.0-32.5 years, range: 12.0-58.0 years). Internal consistency (Cronbach's alpha: 0.83-0.90) and test-retest reliability (intraclass correlation coefficient: 0.90; 95% CI: 0.65-0.92; p < 0.001) of quality of life (Q-Life) scores were strong. Q-Life scores were associated with overall Cystic Fibrosis Questionnaire-Revised (CFQ-R) scores (ρ = 0.71; p < 0.001), CFQ-R respiratory domain scores (ρ = 0.57; p < 0.001) and forced expiratory volume in 1s (ρ = 0.41; p < 0.001). Furthermore, Q-Life scores improved from 65.0 (IQR: 45.0-63.3) at baseline to 84.2 (IQR: 75.0-95.0) and 87.5 (IQR: 75.0-100.0) after 3 and 6 months of elexacaftor/tezacaftor/ivacaftor treatment (change: 20.8; 95% CI: 17.5-25.0; p < 0.001), comparable to CFQ-R respiratory domain scores (change: 22.2, 95% CI: 19.4-25.0, p < 0.001). Interpretation: The Q-Life app is a reliable, valid and sensitive personalized ePROM to measure all aspects of quality of life that really matter to individuals with Cystic Fibrosis. This patient-centered approach could provide important advantages over generic and disease-specific PROMs in the era of personalized medicine and value-based healthcare. Funding: Dutch Cystic Fibrosis Foundation, Health-Holland.

Long-term effectiveness of dual CFTR modulator treatment of cystic fibrosis.

Background: Although short-term efficacy of lumacaftor/ivacaftor and tezacaftor/ivacaftor is clearly established in clinical trials, data on long-term effectiveness is limited. This registry-based cohort study assessed real-world longitudinal outcomes of F508del-homozygous people with cystic fibrosis (pwCF) ≥12 years, up to 3 years after the introduction of dual cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Methods: Annual data (2010-2019) were retrieved from the Dutch Cystic Fibrosis Registry. Longitudinal trends of per cent predicted forced expiratory volume in 1 s (FEV1 % pred) decline, body mass index (BMI), BMI Z-score and intravenous antibiotic treatment duration before and after CFTR modulator initiation were assessed with linear and negative binomial mixed models. Results: We included 401 participants (41.9% female, baseline age 24.5 years (IQR 18.0-31.5 years), baseline mean±sd FEV1 70.5±23.4% pred). FEV1 decline improved from -1.36% pred per year to -0.48% pred per year after modulator initiation (change: 0.88% pred, 95% CI: 0.35-1.39%, p=0.001). This change was even 1.40% pred per year (95% CI: -0.0001-2.82%, p=0.050) higher in participants with baseline FEV1 <40% pred. In adults, annual BMI trend was not altered (change: 0.10 kg·m-2·year-1, 95% CI:-0.01-0.21, p=0.079). Annual BMI Z-score in children reversed from -0.08 per year before modulator treatment to 0.06 per year afterwards (change: 0.14 per year, 95% CI: 0.06-0.22, p<0.001). Intravenous antibiotic treatment duration showed a three-fold reduction in the first year after modulator initiation (incidence rate ratios (IRR): 0.28, 95% CI: 0.19-0.40, p<0.001), but the annual trend did not change in the subsequent years (IRR: 1.19, 95% CI: 0.94-1.50, p=0.153). Conclusion: Long-term effectiveness of dual CFTR modulator therapies on FEV1 decline, BMI and intravenous antibiotic treatment duration is less pronounced in a real-world setting than in clinical trials and varies considerably between pwCF and different baseline FEV1 levels.

Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC). METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC. RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11-0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07-0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06-0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12-0.97; p=0.044). These associations were absent for SCC. CONCLUSION: This study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Long-term expanding human airway organoids for disease modeling.

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

Comparison of ex vivo and in vitro intestinal cystic fibrosis models to measure CFTR-dependent ion channel activity.

BACKGROUND: New functional assays using primary human intestinal adult stem cell cultures can be valuable tools to study epithelial defects in human diseases such as cystic fibrosis. METHODS: CFTR-mediated ion transport was measured in rectal organoid-derived monolayers grown from subjects with various CFTR mutations and compared to donor-matched intestinal current measurements (ICM) in rectal biopsies and forskolin-induced swelling of rectal organoids. RESULTS: Rectal organoid-derived monolayers were generated within four days. Ion transport measurements of CFTR function using these monolayers correlated with ICM and organoid swelling (r = 0.73 and 0.79 respectively). Culturing the monolayers under differentiation conditions enhanced the detection of mucus-secreting cells and was accompanied by reduced CFTR function. CONCLUSIONS: CFTR-dependent intestinal epithelial ion transport properties can be measured in rectal organoid-derived monolayers of subjects and correlate with donor-matched ICM and rectal organoid swelling.

ß2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified ß2-adrenergic receptor agonists as the most potent inducers of CFTR function.ß2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled ß2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

Functional Characterization of Cholera Toxin Inhibitors Using Human Intestinal Organoids.

Preclinical drug testing in primary human cell models that recapitulate disease can significantly reduce animal experimentation and time-to-the-clinic. We used intestinal organoids to quantitatively study the potency of multivalent cholera toxin inhibitors. The method enabled the determination of IC50 values over a wide range of potencies (15 pM to 9 mM). The results indicate for the first time that an organoid-based swelling assay is a useful preclinical method to evaluate inhibitor potencies of drugs that target pathogen-derived toxins.