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2017 ; 9
(9
): 1224-1243
Nephropedia Template TP
gab.com Text
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Twit Text #
English Wikipedia
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.