Abstract
Rationale Given the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF).
Objectives To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.
Methods Intestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature.
Results Across 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.
Conclusions Measurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.
Abstract
Rescue of CFTR function with modulators measured in colon organoids can be used to guide precision medicine in patients with cystic fibrosis. Organoids are an effective model to bring treatment to patients with CF carrying rare CFTR mutations. https://bit.ly/2VHHH6s
Footnotes
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Belgian Organoid Project: Hedwige Boboli (CHR Citadelle, Liège, Belgium), Linda Boulanger (University Hospital Leuven, Belgium), Georges Casimir (HUDERF, Brussels, Belgium), Senne Cuyx (KU Leuven and UZ Leuven, Belgium), Benedicte De Meyere (University Hospital Ghent, Belgium), Elke De Wachter (University Hospital Brussels, Belgium), Danny De Looze (University Hospital Ghent, Belgium), Isabelle Etienne (CHU Erasme, Brussels, Belgium), Laurence Hanssens (HUDERF, Brussels), Christiane Knoop (CHU Erasme, Brussels, Belgium), Monique Lequesne (University Hospital Antwerp, Belgium), Vicky Nowé (vzw Gasthuiszusters Antwerp, Belgium), Stephanie Van Biervliet (University Hospital Ghent, Belgium), Eva Van Braeckel (University Hospital Ghent, Belgium), Kim Van Hoorenbeeck (University Hospital Antwerp, Belgium), Eef Vanderhelst (University Hospital Brussels, Belgium), Stijn Verhulst (University Hospital Antwerp, Belgium), Stefanie Vincken (University Hospital Brussels, Belgium).
Author contributions: Conceptualisation: A.S. Ramalho, F. Vermeulen and K. De Boeck; methodology: A.S. Ramalho, E. Fürstová, J.M. Beekman, A.M. Vonk, C. Vazquez Cordero, M. Ferrante, F. Vermeulen, M. Proesmans, M. Boon and L. Dupont; recruiting of subjects and collection of rectal biopsies: M. Boon, M. Proesmans, F. Vermeulen, C. Vazquez Cordero, L. Dupont and I. Sarouk, Belgian Organoid Project participants; culturing the organoids and performing the FIS assay analysis: A.S. Ramalho and E. Fürstová; analysis of the results and figures preparation: A.S. Ramalho and F. Vermeulen; writing the original draft: A.S. Ramalho, F. Vermeulen and K. De Boeck; review and editing: all; supervision: F. Vermeulen and K. De Boeck.
Conflict of interest: A.S. Ramalho has nothing to disclose.
Conflict of interest: E. Fürstová has nothing to disclose.
Conflict of interest: A.M. Vonk has nothing to disclose.
Conflict of interest: M. Ferrante reports grants and personal fees from Amgen, grants, personal fees and non-financial support from Biogen, Janssen, Pfizer and Takeda, personal fees and non-financial support from Boehringer Ingelheim, MSD, Falk and Ferring, personal fees from Sandoz, Lamepro, and Mylan, outside the submitted work.
Conflict of interest: C. Verfaillie has nothing to disclose.
Conflict of interest: L. Dupont has nothing to disclose.
Conflict of interest: M. Boon is a member of the European Reference Network for Rare Respiratory Diseases (ERN-LUNG) – Project ID number 739546.
Conflict of interest: M. Proesmans has nothing to disclose.
Conflict of interest: J.M. Beekman reports personal fees from various industries (Vertex, Proteostasis, Teva, others) for costs related to conference presentations, outside the submitted work; and has a patent WO2013093812A3 with royalties paid by Hubrecht Organoid Technology.
Conflict of interest: I. Sarouk has nothing to disclose.
Conflict of interest: C. Vazquez Cordero has nothing to disclose.
Conflict of interest: F. Vermeulen has nothing to disclose.
Conflict of interest: K. De Boeck has provided consultancy for Boehringer, Protalix, Raptor, Novabiotics, Eloxx and Chiesi, has been member of steering committees/advisory boards and been PI in studies for Vertex, has provided consultancy and been PI in studies for Galapagos, and has received speaker fees from Teva, outside the submitted work.
Support statement: This study was funded by the Belgian CF patients’ association “Mucovereniging/Association Muco” and the Flemish Research Foundation (FWO – Fonds voor Wetenschappelijk Onderzoek – Vlaanderen – C3 project). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 17, 2019.
- Accepted June 29, 2020.
- Copyright ©ERS 2021