Intestinal organoids grown from rectal biopsies using culture protocols established by the Clevers group have been used to model cystic fibrosis, and led to the first application of organoids for personalised treatment. Cystic fibrosis is an inherited disease that is caused by gene mutations of the cystic fibrosis transmembrane conductance regulator gene that encodes an epithelial ion channel necessary for healthy epithelial surface fluids. Studies by the laboratory of Jeffrey Beekman (Wilhelmina Childrens Hospital, University Medical Center Utrecht, The Netherlands) described in 2013 that stimulation of colorectal organoids with cAMP-raising agonists such as forskolin or cholera toxin induced rapid swelling of organoids in a fully CFTR dependent manner. Whereas organoids from non-cystic fibrosis subjects swell in response to forskolin as a consequence of fluid transport into the organoids lumens, this is severely reduced or absent in organoids derived from people with cystic fibrosis. Swelling could be restored by therapeutics that repair the CFTR protein (CFTR modulators), indicating that individual responses to CFTR modulating therapy could be quantitated in a preclinical laboratory setting. Schwank et al. also demonstrated that the intestinal cystic fibrosis organoid phenotype could be repaired by CRISPR-Cas9 gene editing in 2013.
Follow-up studies by Dekkers et al. in 2016 revealed that quantitative differences in forskolin-induced swelling between intestinal organoids derived from people with cystic fibrosis associate with known diagnostic and prognostic markers such as CFTR gene mutations or in vivo biomarkers of CFTR function. In addition, the authors demonstrated that CFTR modulator responses in intestinal organoids with specific CFTR mutations correlated with published clinical trial data of these treatments. This led to preclinical studies where organoids from patients with extremely rare CFTR mutations for who no treatment was registered were found to respond strongly to a clinically available CFTR modulator. The suggested clinical benefit of treatment for these subjects based on the preclinical organoid test was subsequently confirmed upon clinical introduction of treatment by members of the clinical CF center under supervision of Kors van der Ent (Department of Paediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands). These studies show for the first time that organoids can be used for the individual tailoring of therapy or personalised medicine.