Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene: the gene product responsible for transporting chloride and bicarbonate ions through the apical membrane of most epithelial cells. Major clinical features of CF include respiratory failure, pancreatic exocrine insufficiency, and intestinal disease. Many CF animal models have been generated, but some models fail to fully capture the phenotypic manifestations of human CF disease. Other models that better capture the key characteristics of the human CF phenotype are cost prohibitive or require special care to maintain. Important differences have been reported between the pathophysiology seen in human CF patients and in animal models. These limitations present significant limitations to translational research. This review outlines the study of CF using patient-derived organs-on-a-chip to overcome some of these limitations. Recently developed microfluidic-based organs-on-a-chip provide a human experimental model that allows researchers to manipulate environmental factors and mimic in vivo conditions. These chips may be scaled to support pharmaceutical studies and may also be used to study organ systems and human disease. The use of these chips in CF discovery science enables researchers to avoid the barriers inherent in animal models and promote the advancement of personalized medicine.
Highlights
Board of Governors Regenerative Medicine Institute, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
This report mentioned that higher cystic fibrosis transmembrane regulator (CFTR) expression may be present in the bronchiolar epithelium, but the precise level of CFTR expression was not measured. This combination of findings supports the existence of Cystic fibrosis (CF) pathophysiology in small airways and underscores the need for further studies on the role of CFTR in type I
In the absence of airway inflammation and infection, CFTR−/− pigs display irregularly shaped cartilage and abnormal tracheal smooth muscle [70]. These observations suggest that a defect in CFTR function in the airway smooth muscle (ASM) may contribute to the underlying pathophysiology
Summary
Medical treatment of CF focused on targeting the organ-specific sequelae from the underlying disease [22,23]. FDA approval was ivacaftor (Kalydeco, Vertex Pharmaceuticals, Boston, MA, USA), a CFTR “potentiator” that works by opening the dysfunctional CFTR channel present on the cell surface [24,25,26,27,28,29]. Two key phase III clinical studies showed that treated patients with at least one copy of the G551D CFTR gating mutation had marked improvement in lung function (forced expiratory volume in 1 s (FEV1 )), quality of life, weight, and biomarkers of CFTR function (sweat chloride) [25,28]. The G551D mutation is only present in 5% of the CF population, the success of ivacaftor showed that modulators are effective in rescuing CFTR protein function, opening the door for the discovery of additional novel modulators that may be relevant to a broader population of CF patients
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