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- Title
Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia.
- Authors
Ahmadi, Saumel; Bozoky, Zoltan; Di Paola, Michelle; Xia, Sunny; Li, Canhui; Wong, Amy P.; Wellhauser, Leigh; Molinski, Steven V.; Ip, Wan; Ouyang, Hong; Avolio, Julie; Forman-Kay, Julie D.; Ratjen, Felix; Hirota, Jeremy A.; Rommens, Johanna; Rossant, Janet; Gonska, Tanja; Moraes, Theo J.; Bear, Christine E.
- Abstract
Pulmonary disease is the major cause of morbidity and mortality in patients with cystic fibrosis, a disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Heterogeneity in CFTR genotype–phenotype relationships in affected individuals plus the escalation of drug discovery targeting specific mutations highlights the need to develop robust in vitro platforms with which to stratify therapeutic options using relevant tissue. Toward this goal, we adapted a fluorescence plate reader assay of apical CFTR-mediated chloride conductance to enable profiling of a panel of modulators on primary nasal epithelial cultures derived from patients bearing different CFTR mutations. This platform faithfully recapitulated patient-specific responses previously observed in the "gold-standard" but relatively low-throughput Ussing chamber. Moreover, using this approach, we identified a novel strategy with which to augment the response to an approved drug in specific patients. In proof of concept studies, we also validated the use of this platform in measuring drug responses in lung cultures differentiated from cystic fibrosis iPS cells. Taken together, we show that this medium throughput assay of CFTR activity has the potential to stratify cystic fibrosis patient-specific responses to approved drugs and investigational compounds in vitro in primary and iPS cell-derived airway cultures. Cystic fibrosis: toward personalized therapies A new method for evaluating drug responses in patient-derived respiratory tissue promises to help determine the best treatment for each patient with cystic fibrosis (CF). CF patients are highly susceptible to lung infections due to the build-up of thick mucus in the airways. Over 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified in patients with CF, which partly explains their varied response to treatment. Saumel Ahmadi, Christine E. Bear, and colleagues at the Hospital for Sick Children in Toronto developed a fluorescence-based method for measuring improvements in mutant CFTR function in patient-derived nasal and induced pluripotent stem cell-derived lung tissue. This method enables comparison of approved and investigational drugs on airway cells from each individual patient and in the longer term will accelerate the development of personalized therapeutic strategies.
- Publication
NPJ Genomic Medicine, 2017, Vol 2, Issue 1, pN.PAG
- ISSN
2056-7944
- Publication type
Article
- DOI
10.1038/s41525-017-0015-6