CF Severity Predicted by Forskolin-Induced Swelling in Intestinal Organoids

Forskolin-induced swelling (FIS) in intestinal organoids is a clinically relevant biomarker of cystic fibrosis (CF) disease severity and CF transmembrane conductance regulator (CFTR) function in infants diagnosed with CF, according to the results of a study published in the European Respiratory Journal.

Individuals with CF display considerable variability in organ dysfunction and overall survival. This is caused by differences in the CFTR gene, as more than 2000 CFTR variants have been identified. Additional genetic and environmental factors also play a role. As a result, clinicians face challenges in predicting the clinical course of individuals based on CFTR genotype.

In a proof-of-concept study, researchers from The Netherlands explored whether FIS outcomes correlated with gastrointestinal and pulmonary clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF between May 2011 and January 2015.

The investigators found that FIS of laboratory-grown organoids (created from patient stem cells) occurred in a dose-dependent fashion as well as in a patient- and CFTR-genotype-dependent fashion. Infants with low FIS had higher levels of immunoreactive trypsinogen (IRT; P =.03) and pancreas-associated protein (P =.039) and were more likely to be pancreatic insufficient (P <.001), have abnormalities on chest computed tomography (CT; P =.049), and have lower z-scores for maximal expiratory flow at functional residual capacity (P =.033) compared with children who had high FIS values.

Furthermore, FIS was significantly correlated with sweat-chloride concentration (SCC) and intestinal current measurement (ICM) (r= −0.82 and 0.70, respectively; both P <.001). The study also found that FIS at 0.8 μM identified 2 clusters of infants — with more severe and less severe disease — who mirrored the results of dividing the cohort into subgroups using SCC-based criteria.

The investigators cautioned that studies are necessary in different age groups to establish how well CFTR function can be assessed by FIS, and exact FIS thresholds remain to be determined. However, in most cases the 3 biomarkers of CFTR function — SCC, ICM, and FIS — aligned well and were able to type individuals as classic or severe CF or milder forms of CF.

Several study limitations, including the relatively small patient population, limited clinical follow-up, and a relatively high number of missing ICM measurements were noted. Nonetheless, FIS represents a relatively noninvasive method of assessing CFTR function and response to CFTR-modulating therapy.

The researchers suggested that FIS assay may play a role in both the timing and efficacy of drug treatment in individual patients. Intestinal organoids may be used in the preclinical phases of CFTR modulator development and may be biobanked for future analysis without the need to request further patient samples and cause further patient discomfort.

Reference

de Winter-de Groot KM, Janssens HM, van Uum RT, et al. Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as biomarker of CFTR function [published online August 30, 2018]. Eur Respir J. doi:10.1183/13993003.02529-2017