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Background: The forskolin-induced swelling (FIS) assay measures CFTR function on patient-derived intestinal organoids (PDIOs) and may guide treatment selection for individuals with Cystic Fibrosis (CF). The aim of this study is to demonstrate the repeatability and reproducibility of the FIS assay following a detailed Standard Operating Procedure (SOP), thus advancing the validation of the assay for precision medicine (theranostic) applications., Methods: Over a 2-year period, FIS responses to CFTR modulators were measured in four European labs. PDIOs from six subjects with CF carrying different CFTR genotypes were used to assess the repeatability and reproducibility across the dynamic range of the assay., Results: Technical, intra-assay repeatability was high (Lin's concordance correlation coefficient (CCC) 0.95-0.98). Experimental, within-subject repeatability was also high within each lab (CCCs all >0.9). Longer-term repeatability (>1 year) showed more variability (CCCs from 0.67 to 0.95). The reproducibility between labs was also high (CCC ranging from 0.92 to 0.97). Exploratory analysis also found that between-lab percentage of agreement of dichotomized CFTR modulator outcomes for predefined FIS thresholds ranged between 78 and 100 %., Conclusions: The observed repeatability and reproducibility of the FIS assay within and across different labs is high and support the use of FIS as biomarker of CFTR function in the presence or absence of CFTR modulators., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Patient-derived intestinal organoids (PDIOs) show great potential as in vitro drug testing platform for personalised medicine in Cystic Fibrosis and oncology. PDIOs can be generated by culturing adult stem cells obtained through rectal forceps biopsy or suction biopsy, but the safety of these procedures and the success rates of generating organoids after shipment to a centralized lab using these procedures has not been studied in this context. We here report the safety and success rates of both biopsy procedures and the subsequent generation of PDIOs in the international multicentre HIT-CF Organoid Study., Methods: 502 biopsy procedures were conducted, on 489 adult people with Cystic Fibrosis from 33 different hospitals across 12 countries. Depending on the preference of the hospital, either rectal forceps biopsies or suction biopsies were obtained and internationally shipped to a central laboratory for organoid generation., Results: No adverse events were reported for 280 forceps biopsy procedures, while 222 rectal suction biopsy procedures resulted in 2 adverse events, namely continued bleeding and a probably nonrelated gastroenteritis. The success rate of organoid generation from all biopsies was 95%, and the main reason for failure was insufficient sample viability (3.2%)., Conclusion: Our results indicate that both rectal suction biopsy and forceps biopsy procedures are safe procedures. The high success rates of PDIO generation from the obtained tissue samples demonstrate the feasibility of the organoid technology for personalised in vitro testing in an international setting., Competing Interests: Declaration of competing interest No conflict., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF., Methods: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators., Results: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy., Conclusion: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies., One-Sentence Summary: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes., Competing Interests: Declaration of Competing Interest J.M.B. reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos, outside the submitted work; In addition, J.M.B. has a patent(s) related to the FIS-assay with royalties paid. C.K.v.d.E. reports grants from GSK, grants from Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV and Eloxx outside the submitted work; In addition, C.K.v.d.E. has a patent 10006904 with royalties paid. G.H.K. reports grants from Lung Foundation of the Netherlands, Vertex Pharmaceuticals, UBBO EMMIUS foundation, GSK, TEVA the Netherlands, ZON-MW (Vici-grant), European Union (H2020), outside the submitted work; and he has participated in advisory boards meetings to GSK and PURE-IMS outside the submitted work (Money to institution). All other authors have nothing to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy., (Copyright © 2022. Published by Elsevier B.V.)

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 (FEV 1 pp) 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 FEV 1 pp 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., Competing Interests: Conflict of interest: J.M. Beekman reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos, outside the submitted work; in addition, J.M. Beekman has a patent related to the FIS-assay with royalties paid. C.K. van der Ent reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV and Eloxx, outside the submitted work; in addition, C.K. van der Ent has a patent 10006904 with royalties paid. G.H. Koppelman reports grants from Lung Foundation of the Netherlands, Vertex Pharmaceuticals, UBBO EMMIUS foundation, GSK, TEVA the Netherlands, TETRI Foundation and European Union (H2020), outside the submitted work; and has participated in advisory board meetings for GSK and PURE-IMS outside the submitted work (money paid to institution). P. van Mourik reports financial compensation (money to institution) from Vertex for participation in a webinar, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation., Methods: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV 1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated., Results: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV 1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV 1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively., Conclusions: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV 1 ) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331)., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: JRD, ZY, and NK are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated; PA was employed by Vertex Pharmaceuticals Incorporated at the time the study was conducted; HH reports personal fees from Gilead, PTC, Teva, and Vertex Pharmaceuticals Incorporated, and clinical trials with AbbVie and Vertex Pharmaceuticals Incorporated; JMB reports grants from Eloxx and Proteostasis, travel support from Proteostasis and Vertex Pharmaceuticals Incorporated, and royalties from the Royal Netherlands Academy of Sciences and Arts; RGJV is the CEO of Hubrecht Organoid Technology, a company based on the commercial implementation of the organoid technology, and reports grants and advisory board membership from Vertex Pharmaceuticals Incorporated; CKvdE reports grants from Eloxx, Galapagos NV, Gilead, GSK, Nutricia, ProQR, Proteostasis, Teva, and Vertex Pharmaceuticals Incorporated, and a patent (10006904) with royalties paid. SFB does not have any other disclosures to report., (Copyright © 2020. Published by Elsevier B.V.)

Background: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations., Methods: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids., Results: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma., Conclusions: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed., Competing Interests: Declaration of Competing Interest J.M.B. and C.K.v.d.E are inventors on a patent application related to these findings. GHK reports research funding from the Lung Foundation of the Netherlands, GSK, Ubbo Emmius Foundation, Vertex, TEVA the Netherlands, TETRI Foundation, outside the submitted work and participation in advisory boards from GSK and PureIMS, outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Variability in disease severity and CFTR modulator responses exists between patients with identical CFTR genotypes. Here, we characterized transcription, translation and function of R117H-CFTR using intestinal organoids and correlated them with in vitro responses to ivacaftor (VX-770)., Methods: Organoids were generated from individuals possessing at least one R117H-CFTR allele. The forskolin-induced swelling (FIS) assay was used to measure CFTR function and response to VX-770 treatment. R117H-CFTR protein and mRNA expression levels were determined in parallel and Pearson's correlation coefficients were assessed., Results: Variability in R117H-CFTR FIS responses was observed and correlated significantly with mRNA and protein expression. Response to VX-770 treatment in organoids correlated with mRNA and protein expression as well., Conclusions: Our results indicate that gene expression, protein expression and CFTR function are strongly correlated in organoids from people with CFTR-R117H-7T/9T, which may suggest that CFTR gene expression may have consequences for CF diagnosis, prognosis and therapeutic benefit., Competing Interests: Declaration of Competing Interest Cornelis K. van der Ent reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV, and grants from Eloxx outside the submitted work and has a patent 10006904 with royalties paid. Prof. Dr. Beekman has a patent on organoid swelling for personalized diagnosis in CF with royalties paid to Hubrecht Organoid Technology and received financial support to cover travel costs and preparation time of scientific lectures from Vertex Pharmaceuticals. He also received funding from Galápagos NV for CFTR modulator studies., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

This protocol describes the isolation, handling, culture of, and experiments with human colon stem cell organoids in the context of cystic fibrosis (CF). In human colon organoids, the function of cystic fibrosis transmembrane conductance regulator (CFTR) protein and its rescue by CFTR modulators can be quantified using the forskolin-induced swelling assay. Implementation procedures and validation experiments are described for six CF human colon organoid lines, and representative CFTR genotypes are tested for basal CFTR function and response to CFTR-modulating drugs. For complete details on the use and execution of this protocol, please refer to Dekkers et al (2016) and Berkers and van Mourik (2019)., Competing Interests: J.F.D. is an inventor on a patent related to the organoid technology. M.A.A. reports grants from Gilead Pharmaceuticals, Vertex Pharmceuticals, Proteostasis Therapeutics and personal fees from Vertex Pharmceuticals and PTC Pharmaceuticals outside the submitted work. K.B. reports consultancy work for CHIESI, grants from VERTEX, advisory board meetings for PROTEOSTASIS and ELOXX, grants from and advisory board meetings for GALAPAGOS, and advisory board meetings for TRANSLATE BIO outside the submitted work. R.V. is CEO of Hubrecht Organoid Technology, which provides organoid services to companies. C.K.E. reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV, and Eloxx outside the submitted work and has a patent 10006904 with royalties paid. J.M.B. is inventor on a patent related to CFTR function measurements in organoids and has received financial royalties. He also participates in industry-sponsored clinical trials (Galapagos NV, Vertex Pharmaceuticals, Proteostasis, Eloxx Pharmaceuticals) and has received travel reimbursements and speaker’s fees. The other authors have nothing to disclose., (© 2020 The Authors.)

Adenine base editing (ABE) enables enzymatic conversion from A-T into G-C base pairs. ABE holds promise for clinical application, as it does not depend on the introduction of double-strand breaks, contrary to conventional CRISPR/Cas9-mediated genome engineering. Here, we describe a cystic fibrosis (CF) intestinal organoid biobank, representing 664 patients, of which ~20% can theoretically be repaired by ABE. We apply SpCas9-ABE (PAM recognition sequence: NGG) and xCas9-ABE (PAM recognition sequence: NGN) on four selected CF organoid samples. Genetic and functional repair was obtained in all four cases, while whole-genome sequencing (WGS) of corrected lines of two patients did not detect off-target mutations. These observations exemplify the value of large, patient-derived organoid biobanks representing hereditary disease and indicate that ABE may be safely applied in human cells., Competing Interests: Declaration of Interests J.M.B. is an inventor on (a) patent(s) related to the FIS assay and received financial royalties from 2017 onward. J.M.B. reports receiving (a) research grant(s) and consultancy fees from various industries, including Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries, and Galapagos outside the submitted work. H.C. holds several patents on organoid technology. Their application numbers, followed by their publication numbers (if applicable), are as follows: PCT/NL2008/050543, WO2009/022907; PCT/NL2010/000017, WO2010/090513; PCT/IB2011/002167, WO2012/014076; PCT/IB2012/052950, WO2012/168930; PCT/EP2015/060815, WO2015/173425; PCT/EP2015/077990, WO2016/083613; PCT/EP2015/077988, WO2016/083612; PCT/EP2017/054797, WO2017/149025; PCT/EP2017/065101, WO2017/220586; PCT/EP2018/086716, n/a; and GB1819224.5, n/a., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: P. van Mourik has nothing to disclose. Conflict of interest: J.M. Beekman has a patent on organoid swelling for personalised diagnosis in CF with royalties paid by Hubrecht Organoid Technology. He received financial support to cover travel costs and preparation time of scientific lectures from Vertex. He also received funding from Galapagos for CFTR modulator studies. Conflict of interest: C.K. van der Ent reports grants from Vertex Pharmaceuticals Inc, Gilead Sciences and Galapagos, grants and other funding from ProQR, and other funding from TEVA pharmaceutical industries, outside the submitted work.

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Abstract Background Cystic fibrosis is a rare recessive monogenic disease caused by loss-of-function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Recently developed CFTR-modulators (i.e. drugs that rescue CFTR-function) have improved the prognosis of the disease, but are only available for certain, relatively common mutations. More than 2000 genetic variants in CFTR have been described, many of which are uncharacterized, while efficacy of CFTR-modulators can differ depending on genotype. Personalized models that can predict drug efficacy in patients with rare mutations could help to provide access to effective CFTR-modulator treatment. The forskolin induced swelling (FIS) assay in rectal organoids can robustly measure CFTR-function and CFTR-modulator efficacy, and pilot studies indicate that FIS accurately predicts treatment efficacy in individual patients. In the HIT-CF Organoid Study, rectal organoids from patients with rare CFTR-mutations are screened for CFTR-modulator efficacy to identify patients that could clinically benefit from these drugs. Methods In this EU-H2020 funded multi-centre study, rectal biopsies are obtained from approximately 500 subjects with rare CFTR-mutations from 17 different EU countries and sent to central laboratories. Organoids are generated, on which several novel CFTR-modulating drugs are screened for efficacy. In the process, a biobank is generated which could be used for future research. Subjects whose organoids show a response to treatment will be asked to participate in subsequent clinical trials evaluating the clinical efficacy of tested drugs. Discussion The HIT-CF Organoid Study applies the intestinal organoid model for personalized medicine in patients with rare variant cystic fibrosis, who are currently excluded from classical CFTR-modulator trials. Together with the subsequent clinical trials in high responders, this study aims to create a new pathway for access to CFTR-modulating drugs for patients with ultra-rare CFTR variants. Trial registration This trial has been registered in the Netherlands Trial Registry (NTR7520, https://www.trialregister.nl/trial/7304 ), a primary registry approved and recognized by WMO and ICMJE, on 2018-10-02.

Cystic fibrosis (CF) is a multiorgan disorder, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in abnormal regulation of salt and water movement across membranes. In the liver this leads to hyperviscous bile accumulating in the biliary tree, causing cholangiocyte and hepatocyte injury and inflammation, stimulating focal fibrosis. With increased life expectancy CF related liver disease (CFLD) has become a leading cause of morbidity and mortality in patients with CF. Most patients with CFLD remain asymptomatic even though approximately 5–10% develop multilobular cirrhosis during the first decade of life. Most will develop signs of portal hypertension. Active screening for CFLD and introduction of non-invasive imaging techniques and novel biomarkers would identify individuals at risk for cirrhosis prior to its development in order to institute therapy to prevent or reduce disease progression, and can detect patients who have developed clinically silent cirrhosis to allow monitoring and interventions to reduce or mitigate complications. Liver transplant should be considered for those who develop hepatic dysfunction or advanced portal hypertension, although deteriorating pulmonary function and quality of life should also be taken into account. Current research in CFLD focuses on repairing the basic defect and reducing inflammation thus aiming to find treatment modalities that prevent development and/or progression of CLFD. [ABSTRACT FROM AUTHOR]