Personalised CFTR pharmacotherapeutic response testing and therapy of cystic fibrosis. Issue 6 (7th June 2018)

• Record Type: Journal Article
• Authors: McCarthy, Cormac; Brewington, John J.; Harkness, Beth; Clancy, John P.; Trapnell, Bruce C.
• Is Part Of: European respiratory journal. Volume 51:Issue 6(2018)
• Publication Date: 2018-06-07
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.02457-2017
• Languages: English
• ISSNs: 0903-1936

Abstract

Cystic fibrosis (CF) is a fatal, multisystem, genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride transporter critical to luminal fluid homeostasis at respiratory airway and other ductal epithelial surfaces. Therapeutic options for some CF patients were transformed by the approval of ivacaftor and lumacaftor/ivacaftor, which are indicated, respectively, for patients heterozygous for a subset of rare class III mutations [1] or homozygous for the common class II mutation Phe508del [2]. Notwithstanding, more than 40% of CF patients do not meet the CFTR mutation-specific inclusion criteria and are excluded from these therapies and, while it is impractical to conduct a clinical trial for each new pharmacotherapy-responsive CFTR mutation identified, an evolution of the drug approval process now permits drug label expansion based on in vitro physiological response testing. Indeed, the development of novel patient cell-based methods such as cultured intestinal organoids [3, 4] or nasal epithelial spheroids [5] permit in vitro testing of targeted CFTR molecular therapies. Here, we report the use of a novel preclinical test in one such patient to demonstrate patient-specific functional correction of CFTR ex vivo followed by initiation of therapy and functional correction in vivo . Further, while adverse respiratory effects have been reported with lumacaftor/ivacaftor therapy [6], a comprehensive description of the treatment adjustment period has not been previously reported, here we provide a detailed account of this phenomenon. Pharmacotherapeutic response testing identified CFTR Ser1159Pro as responsive to cystic fibrosis modulator therapy http://ow.ly/dvsq30jcBMw