@article{
 title = {Orkambi ® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue},
 type = {article},
 year = {2017},
 keywords = {3700 a,amplifier,c,cas 9,cftr,crispr,cystic fibrosis,g,gene therapy,genetic disease,respiratory,subject categories genetics},
 pages = {1-20},
 id = {9b79cfe0-ed99-3ca4-91f5-f879158cac03},
 created = {2017-07-08T04:36:12.907Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-07-08T04:38:34.228Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 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.},
 bibtype = {article},
 author = {Molinski, Steven V and Ahmadi, Saumel and Ip, Wan and Ouyang, Hong and Villella, Adriana and Miller, John P and Lee, Po-shun and Kulleperuma, Kethika and Du, Kai and Paola, Michelle Di and Eckford, Paul D W and Laselva, Onofrio and Huan, Ling Jun and Wellhauser, Leigh and Li, Ellen and Ray, Peter N and Pomès, Régis and Moraes, Theo J and Gonska, Tanja and Ratjen, Felix and Bear, Christine E},
 doi = {10.15252/emmm.201607137},
 journal = {EMBO Molecular Medicine}
}

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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.","bibtype":"article","author":"Molinski, Steven V and Ahmadi, Saumel and Ip, Wan and Ouyang, Hong and Villella, Adriana and Miller, John P and Lee, Po-shun and Kulleperuma, Kethika and Du, Kai and Paola, Michelle Di and Eckford, Paul D W and Laselva, Onofrio and Huan, Ling Jun and Wellhauser, Leigh and Li, Ellen and Ray, Peter N and Pomès, Régis and Moraes, Theo J and Gonska, Tanja and Ratjen, Felix and Bear, Christine E","doi":"10.15252/emmm.201607137","journal":"EMBO Molecular Medicine","bibtex":"@article{\n title = {Orkambi ® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue},\n type = {article},\n year = {2017},\n keywords = {3700 a,amplifier,c,cas 9,cftr,crispr,cystic fibrosis,g,gene therapy,genetic disease,respiratory,subject categories genetics},\n pages = {1-20},\n id = {9b79cfe0-ed99-3ca4-91f5-f879158cac03},\n created = {2017-07-08T04:36:12.907Z},\n file_attached = {true},\n profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},\n last_modified = {2017-07-08T04:38:34.228Z},\n read = {false},\n starred = {false},\n authored = {true},\n confirmed = {true},\n hidden = {false},\n private_publication = {false},\n 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.},\n bibtype = {article},\n author = {Molinski, Steven V and Ahmadi, Saumel and Ip, Wan and Ouyang, Hong and Villella, Adriana and Miller, John P and Lee, Po-shun and Kulleperuma, Kethika and Du, Kai and Paola, Michelle Di and Eckford, Paul D W and Laselva, Onofrio and Huan, Ling Jun and Wellhauser, Leigh and Li, Ellen and Ray, Peter N and Pomès, Régis and Moraes, Theo J and Gonska, Tanja and Ratjen, Felix and Bear, Christine E},\n doi = {10.15252/emmm.201607137},\n journal = {EMBO Molecular Medicine}\n}","author_short":["Molinski, S., V.","Ahmadi, S.","Ip, W.","Ouyang, H.","Villella, A.","Miller, J., P.","Lee, P.","Kulleperuma, K.","Du, K.","Paola, M., D.","Eckford, P., D., W.","Laselva, O.","Huan, L., J.","Wellhauser, L.","Li, E.","Ray, P., 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