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10.15252/emmm.201607137

http://scihub22266oqcxt.onion/10.15252/emmm.201607137
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suck abstract from ncbi


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pmid28667089
      EMBO+Mol+Med 2017 ; 9 (9 ): 1224-1243
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  • Orkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue #MMPMID28667089
  • Molinski SV ; Ahmadi S ; Ip W ; Ouyang H ; Villella A ; Miller JP ; Lee PS ; Kulleperuma K ; Du K ; Di Paola M ; Eckford PD ; Laselva O ; Huan LJ ; Wellhauser L ; Li E ; Ray PN ; Pomès R ; Moraes TJ ; Gonska T ; Ratjen F ; Bear CE
  • EMBO Mol Med 2017[Sep]; 9 (9 ): 1224-1243 PMID28667089 show ga
  • The combination therapy of lumacaftor and ivacaftor (Orkambi(®)) is approved for patients bearing the major cystic fibrosis (CF) mutation: ?F508 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 ?F508-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.
  • |*Genetic Therapy [MESH]
  • |Aminophenols/*administration & dosage [MESH]
  • |Aminopyridines/*administration & dosage [MESH]
  • |Benzodioxoles/*administration & dosage [MESH]
  • |Combined Modality Therapy [MESH]
  • |Cystic Fibrosis Transmembrane Conductance Regulator/*genetics/metabolism [MESH]
  • |Cystic Fibrosis/*drug therapy/genetics/metabolism [MESH]
  • |Drug Combinations [MESH]
  • |Gene Editing [MESH]
  • |Humans [MESH]
  • |Point Mutation [MESH]


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