• Yu-Sheng Wu, Janet Jiang, Saumel Ahmadi, Alexandria Lew, Onofrio Laselva, Sunny Xia, Claire Bartlett, Wan Ip, Leigh Wellhauser, Hong Ouyang, Tanja Gonska, Theo J Moraes, and Christine E Bear.
• Programmes in Translational Medicine (Y.-S.W., C.B., W.I., H.O., T.G., T.J.M.) and Molecular Medicine (Y.-S.W., J.J., S.A., A.L., O.L., S.X., L.W., C.E.B.), Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; and Departments of Laboratory Medicine and Pathobiology (T.J.M.), Biochemistry (C.E.B.), Physiology (Y.-S.W., S.A., O.L., S.X., C.E.B.), and Paediatrics (T.G., T.J.M.), University of Toronto, Toronto, Ontario, Canada.
• Mol. Pharmacol. 2019 Oct 1; 96 (4): 515-525.

AbstractORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis-causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine whether strategies aimed at increasing arginine would enhance F508del-cystic fibrosis transmembrane conductance regulator (CFTR) channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI on F508del-CFTR-mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI-mediated increases in ciliary beat frequency and mucociliary movement, two in vitro CF phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate the arginine-nitric oxide pathway in combination with CFTR modulators may lead to improved clinical outcomes. SIGNIFICANCE STATEMENT: These proof-of-concept studies highlight the potential to boost the response to cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, lumacaftor and ivacaftor, in patient-derived airway tissues expressing the major CF-causing mutant, F508del-CFTR, by enhancing other regulatory pathways. In this case, we observed enhancement of pharmacologically rescued F508del-CFTR by arginine-dependent, nitric oxide signaling through inhibition of endogenous arginase activity.Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

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