PMID- 35086832
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20220913
IS  - 1399-3003 (Electronic)
IS  - 0903-1936 (Print)
IS  - 0903-1936 (Linking)
VI  - 60
IP  - 2
DP  - 2022 Aug
TI  - Forskolin-induced organoid swelling is associated with long-term cystic fibrosis 
      disease progression.
LID - 10.1183/13993003.00508-2021 [doi]
LID - 2100508
AB  - 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 microM 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.
CI  - Copyright (c)The authors 2022.
FAU - Muilwijk, Danya
AU  - Muilwijk D
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - These authors contributed equally to this work.
FAU - de Poel, Eyleen
AU  - de Poel E
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
AD  - These authors contributed equally to this work.
FAU - van Mourik, Peter
AU  - van Mourik P
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
FAU - Suen, Sylvia W F
AU  - Suen SWF
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
FAU - Vonk, Annelotte M
AU  - Vonk AM
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
FAU - Brunsveld, Jesse E
AU  - Brunsveld JE
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
FAU - Kruisselbrink, Evelien
AU  - Kruisselbrink E
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
FAU - Oppelaar, Hugo
AU  - Oppelaar H
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
FAU - Hagemeijer, Marne C
AU  - Hagemeijer MC
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
AD  - Center for Lysosomal and Metabolic Diseases, Dept of Clinical Genetics, Erasmus 
      University Medical Center, Rotterdam, The Netherlands.
FAU - Berkers, Gitte
AU  - Berkers G
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
FAU - de Winter-de Groot, Karin M
AU  - de Winter-de Groot KM
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
FAU - Heida-Michel, Sabine
AU  - Heida-Michel S
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
FAU - Jans, Stephan R
AU  - Jans SR
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
FAU - van Panhuis, Hannah
AU  - van Panhuis H
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
FAU - van der Eerden, Menno M
AU  - van der Eerden MM
AD  - Dept of Pulmonology, Erasmus MC, University Medical Center, Rotterdam, The 
      Netherlands.
FAU - van der Meer, Renske
AU  - van der Meer R
AD  - Haga Teaching Hospital, The Hague, The Netherlands.
FAU - Roukema, Jolt
AU  - Roukema J
AD  - Radboud University Medical Center, Radboud Institute for Health Sciences, 
      Nijmegen, The Netherlands.
FAU - Dompeling, Edward
AU  - Dompeling E
AD  - Maastricht University Medical Center, Maastricht, The Netherlands.
FAU - Weersink, Els J M
AU  - Weersink EJM
AD  - Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands.
FAU - Koppelman, Gerard H
AU  - Koppelman GH
AUID- ORCID: 0000-0001-8567-3252
AD  - University of Groningen, University Medical Center Groningen, Beatrix Children's 
      Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, 
      Groningen, The Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Groningen Research 
      Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.
FAU - Vries, Robert
AU  - Vries R
AD  - Hubrecht Organoid Technology (HUB), Utrecht, The Netherlands.
FAU - Zomer-van Ommen, Domenique D
AU  - Zomer-van Ommen DD
AD  - Dutch Cystic Fibrosis Foundation (NCFS), Baarn, The Netherlands.
FAU - Eijkemans, Marinus J C
AU  - Eijkemans MJC
AD  - Dept of Data Science and Biostatistics, Julius Center for Health Sciences and 
      Primary Care, University Medical Center, Utrecht University, Utrecht, The 
      Netherlands.
FAU - van der Ent, Cornelis K
AU  - van der Ent CK
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands.
AD  - C.K. van der Ent and J.M. Beekman contributed equally to this article as lead 
      authors and supervised the work.
FAU - Beekman, Jeffrey M
AU  - Beekman JM
AD  - Dept of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, 
      University Medical Center, Utrecht University, Utrecht, The Netherlands 
      J.Beekman@umcutrecht.nl.
AD  - Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 
      Utrecht, The Netherlands.
AD  - Center for Living Technologies, University Medical Center, Utrecht, The 
      Netherlands.
AD  - C.K. van der Ent and J.M. Beekman contributed equally to this article as lead 
      authors and supervised the work.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220818
PL  - England
TA  - Eur Respir J
JT  - The European respiratory journal
JID - 8803460
RN  - 0 (Biomarkers)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - 1F7A44V6OU (Colforsin)
SB  - IM
MH  - Biomarkers
MH  - Colforsin/pharmacology
MH  - *Cystic Fibrosis/complications/genetics
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/genetics
MH  - Disease Progression
MH  - *Exocrine Pancreatic Insufficiency/complications
MH  - Humans
MH  - Mutation
MH  - Organoids
PMC - PMC9386333
COIS- 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.
EDAT- 2022/01/29 06:00
MHDA- 2022/08/23 06:00
PMCR- 2022/08/18
CRDT- 2022/01/28 05:51
PHST- 2021/02/17 00:00 [received]
PHST- 2021/12/23 00:00 [accepted]
PHST- 2022/01/29 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/01/28 05:51 [entrez]
PHST- 2022/08/18 00:00 [pmc-release]
AID - 13993003.00508-2021 [pii]
AID - ERJ-00508-2021 [pii]
AID - 10.1183/13993003.00508-2021 [doi]
PST - epublish
SO  - Eur Respir J. 2022 Aug 18;60(2):2100508. doi: 10.1183/13993003.00508-2021. Print 
      2022 Aug.