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ABSTRACT
Introduction: Cystic fibrosis (CF) is the most fatal autosomal recessive disorder caused by the absence/dysfunction of the CF transmembrane conductance regulator (CFTR) protein at the apical membrane of epithelial cells. The variety of innovative drug- and gene-based approaches warrants the development of assays that can allow disease modeling and high-throughput screening of drugs.
Areas covered: This article aims to highlight the role of stem cells in the development of models that can recapitulate the pathophysiology of CF in the lungs, pancreas, liver, and gut. Particular emphasis will be placed upon the use of these models, derived from induced pluripotent stem cells (iPSCs) and adult stem cells, in the screening of innovative drugs that are in the development pipeline.
Expert opinion: iPSCs and adult stem cells have allowed the reconstitution of facets of CF disease in vitro and in vivo models, and, when converted to organoids, have been successfully employed for the screening of drug and gene therapies across CF patients with both common and rare CFTR mutations. These systems can be further optimized for establishing a correlation between ex-vivo effects and in vivo responses in patients and offer an unprecedented opportunity to realize a personalized approach to the treatment of CF.
Article highlights
Cystic fibrosis (CF) is a life-threatening autosomal recessive disorder due to mutations in the CF transmembrane conductance regulator (CFTR) gene, with clinical manifestations in the lung, pancreas, liver, and gut. Accumulation of sticky mucus in these organs leads to devastating inflammation and ensuing tissue damage.
A myriad of innovative pharmaceuticals and gene-based therapeutic approaches targeted to correct the basic defect in CFTR are being introduced. Along with the occurrence of more than 2,000 mutations and variants in the CFTR gene, innovative models and assays are required in order to study the accessibility of common and rare mutations to these treatments. The label of ivacaftor, the first personalized medicine in CF, has been extended to patients with numerous additional mutations, based not on clinical data but on ex-vivo assay data.
Due to its pathological features, CF is a disease susceptible to treatment with a stem cell-based approach, which can be used independently of mutation class. Stem cells display features that allow them to recapitulate organ physiology in a dish and in animal models, as well as to screen for drugs or genetic therapies. In particular, induced pluripotent stem cells (iPSCs), generated from each individual patient, can recapitulate organ development and promise to become a platform useful for patient stratification in the context of therapeutic interventions.
Adult stem/progenitor cells obtained from rectal and small intestine can form in-vitro organoids that can assist, through forskolin-induced swelling, with drug screening and identification of patients with orphan mutations that could benefit from approved treatments.
Mesenchymal stem cells (MSCs) obtained from fetal and adult tissues can lead to recovery of CF-associated defects in vitro and in vivo and will be the focus of future studies for regenerative medicine approaches aimed at resolving inflammation and infection as well as repairing epithelia.
This box summarizes key points contained in the article.
Declaration of interest
S Castellani is a researcher funded by the intervento Cofinanziato dal Fondo di Sviluppo e Coesione 2007–2013 – APQ Ricera Regione Puglia ‘Programma regionale a sostegno della specializzazione intelligente e delle sostenibilità sociale ed ambientali – Future in Research’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.