Orkambi® and amplifier co‐therapy improves function from a rare CFTR mutation in gene‐edited cells and patient tissue

Autor: Steven V Molinski, Saumel Ahmadi, Wan Ip, Hong Ouyang, Adriana Villella, John P Miller, Po‐Shun Lee, Kethika Kulleperuma, Kai Du, Michelle Di Paola, Paul DW Eckford, Onofrio Laselva, Ling Jun Huan, Leigh Wellhauser, Ellen Li, Peter N Ray, Régis Pomès, Theo J Moraes, Tanja Gonska, Felix Ratjen, Christine E Bear
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 9, Iss 9, Pp 1224-1243 (2017)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.201607137
Popis: Abstract The combination therapy of lumacaftor and ivacaftor (Orkambi®) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508. It has been predicted that Orkambi® could treat patients with rarer mutations of similar “theratype”; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function—similar to ΔF508‐CFTR, are unlikely to yield a robust Orkambi® response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient‐derived tissue. A CRISPR/Cas9‐edited bronchial epithelial cell line bearing this mutation enabled studies showing that an “amplifier” compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi® response. Importantly, this “amplifier” effect was recapitulated in patient‐derived nasal cultures—providing the first evidence for its efficacy in augmenting Orkambi® in tissues harboring a rare CF‐causing mutation. We propose that this multi‐disciplinary approach, including creation of CRISPR/Cas9‐edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations.
Databáze: Directory of Open Access Journals
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