biostudies-literatureMolinski SVCystic Fibrosis CanadaHospital for Sick ChildrenCanadian Institutes of Health ResearchCIHR1224-1243https://www.ebi.ac.uk/biostudies/studies/S-EPMC5582412biostudies-literatureUnknown9(9)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 paEMBO molecular medicineOrkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue.PMC5582412MOP‐130461GPG‐102171CIHR GPG‐102171CIHR MOP‐130461CIHR MOP‐97954MOP‐97954Ratjen FPomes RDi Paola MLi EWellhauser LAhmadi SVillella ALaselva ORay PNBear CEOuyang HHuan LJGonska TEckford PDLee PSMolinski SVIp WDu KMiller JPKulleperuma KMoraes TJfalseOrkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue.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 pa2017-01-01T00:00:00Z2017 Sep2026-04-30T14:45:01.772Z2019-03-27T02:55:19ZS-EPMC55824122866708910.15252/emmm.201607137