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.
Bibliographical noteFunding Information:
This work was funded by grants of the Dutch Cystic Fibrosis Foundation (NCFS) as part of the HIT-CF Program and by ZonMW. Funding information for this article has been deposited with the Crossref Funder Registry.
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.
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