Organoid Technology and Its Role for Theratyping Applications in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is a autosomal recessive, multisystemic disease caused by different mutations in the CFTR gene encoding CF transmembrane conductance regulator. Although symptom management is important to avoid complications, the approval of CFTR modulator drugs in the clinic has demonstrated significant improvements by targeting the primary molecular defect of CF and thereby preventing problems related to CFTR deficiency or dysfunction. CFTR modulator therapies have positively changed the patients’ quality of life, especially for those who start their use at the onset of the disease. Due to early diagnosis with the implementation of newborn screening programs and considerable progress in the treatment options, nowadays pediatric mortality was dramatically reduced. In any case, the main obstacle to treat CF is to predict the drug response of patients due to genetic complexity and heterogeneity. Advances in 3D culture systems have led to the extrapolation of disease modeling and individual drug response in vitro by producing mini organs called “organoids” easily obtained from nasal and rectal mucosa biopsies. In this review, we focus primarily on patient-derived intestinal organoids used as in vitro model for CF disease. Organoids combine high-validity of outcomes with a high throughput, thus enabling CF disease classification, drug development and treatment optimization in a personalized manner.

The case of the missing mouse—developing cystic fibrosis drugs without using animals

“…Organoids are three dimensional structures, so that when CFTR is active, fluid influx leads to swelling of the organoid and measuring the volume of the organoid is a simple way to know whether the drug applied to the organoid is activating CFTR (where increased volume indicates active CFTR). Using this approach, patient-specific theratyping is possible, where organoids from patients can be screened against multiple compounds, or combinations of compounds, to find the optimal dose and identity of drugs to give each individual patient (Clancy et al, 2019;Conti et al, 2022). The major advantage is that the organoid retains the exact same genetic mutation in CFTR as the person, and so "treating" the organoid reflects what will happen in that individual.…”

Pathophysiology of Cystic Fibrosis Liver Disease

“…As such, patients with advanced CFLD may have future therapeutic options to restore hepatobiliary function in addition to the use of modulator drug regimens. This concept will increasingly center on the personalized medicine paradigm of characterizing an individual's disease risk based on assays using patient biospecimens 68,69 . However, the ability to harness these methods to benefit patients with liver involvement will depend on continuous improvements in the understanding of key pathophysiologic mechanisms of CHBHI, to determine the optimal method and timing to intervene throughout natural history of the disease.…”

“…This concept will increasingly center on the personalized medicine paradigm of characterizing an individual's disease risk based on assays using patient biospecimens. 68,69 However, the ability to harness these methods to benefit patients with liver involvement will depend on continuous improvements in the understanding of key pathophysiologic mechanisms of CHBHI, to determine the optimal method and timing to intervene throughout natural history of the disease. Finally, the paradigm of individual, personalized medicine is tailor-made for CF.…”

Therapeutic potential of phytochemicals for cystic fibrosis

“…35,36 Human bronchial epithelia, human nasal epithelia, intestinal organoids (OGs), and nasal, as well as lung spheroids, which represent ex-vivo patient-derived samples, resemble the morphology and functionality of the parent organ epithelium and reflect the complete genetic background of the patient. 36 OGs grown from stem cells, F I G U R E 4 Shows cystic fibrosis complications with organs and their adverse events, and treatment options. NSAID, nonsteroidal antiinflammatory drugs.…”

“…Precision medicine that involves pre‐evaluation of CFTR modulators directly on the patient's tissues ex vivo to determine the response of the modulators on rare CFTR pathogenic variants is often referred to as theratyping 35,36 . Human bronchial epithelia, human nasal epithelia, intestinal organoids (OGs), and nasal, as well as lung spheroids, which represent ex‐vivo patient‐derived samples, resemble the morphology and functionality of the parent organ epithelium and reflect the complete genetic background of the patient 36 . OGs grown from stem cells, which are derived from biopsies, serve as a model to investigate the efficacy of CFTR modulators on an individual basis using the forskolin‐induced swelling assay 14 .…”