Cystic fibrosis: patients' respiratory cells reprogrammed to test more effective drugs
The study, published in the prestigious European Respiratory Journal and coordinated by Marco Lucarelli of the Department of Experimental Medicine of Sapienza University of Rome and Adriana Eramo of the Istituto Superiore di Sanità (ISS), highlighted the possibility of expanding respiratory stem cells from the nasal epithelium of any patient with cystic fibrosis in culture, with great efficiency and in large quantities, using a new cell reprogramming approach.
From these respiratory stem cells, so-called ex vivo disease models can be obtained using special differentiation cultures for respiratory cells and generating organoids that reproduce the patient's defective respiratory tissue in miniaturised, three-dimensional form.
"Using these models," says Marco Lucarelli, 'it has been possible to further investigate the diagnosis and characterisation of the patients' genotypes and to outline the relationship between genotype (the set of genetic variants of the disease) and phenotype (the set of physical characters determined by the mutations) by assessing the effects of specific gene mutations on the corresponding defective proteins in the cells of each patient".
The study evaluated the efficacy of specific drugs in correcting the mutated CFTR protein (responsible for the disease) and restoring its functionality. In particular, the efficacy of the drug (a combination of ivacaftor, tezacaftor and elexacaftor) recently approved in Italy for some of the most frequent mutations was highlighted on three specific rare genetic variants of the disease that are still without a cure.
The approach described, and in particular the organoids originating from the nasal epithelium, were found to be extremely suitable for pharmacological assays and may allow, in future studies, to identify, validate and propose more effective and personalised treatments for all patients with cystic fibrosis.
"In addition, drugs already available for some patients with specific genotypes and others to come", Lucarelli adds, "can be rapidly evaluated in these models and eventually proposed, after screening by regulatory bodies, for cystic fibrosis variants that are responsive ex vivo, guiding customised therapy".
Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells - Giovanni Sette, Stefania Lo Cicero, Giovanna Blaconà, Silvia Pierandrei, Sabina Maria Bruno, Valentina Salvati, Germana Castelli, Mario Falchi, Benedetta Fabrizzi, Giuseppe Cimino, Ruggero De Maria, Mauro Biffoni, Adriana Eramo, Marco Lucarelli European Respiratory Journal DOI: 10.1183/13993003.00908-2021
Department of Experimental Medicine