RT Journal Article
SR Electronic
T1 A helper-dependent adenoviral vector rescues CFTR to wild type functional levels in CF epithelial cells harbouring class I mutations
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2000205
DO 10.1183/13993003.00205-2020
A1 Huibi Cao
A1 Hong Ouyang
A1 Onofrio Laselva
A1 Claire Bartlett
A1 Zhichang Peter Zhou
A1 Cathleen Duan
A1 Tarini Gunawardena
A1 Julie Avolio
A1 Christine E. Bear
A1 Tanja Gonska
A1 Jim Hu
A1 Theo J. Moraes
YR 2020
UL http://erj.ersjournals.com/content/early/2020/05/22/13993003.00205-2020.abstract
AB Cystic Fibrosis (CF) is a genetic disorder affecting multiple organs, including the pancreas, hepatobiliary system and reproductive organs however lung disease is responsible for the majority of morbidity and mortality. Management of CF involves CFTR modulator agents including corrector drugs to augment cellular trafficking of mutant CFTR as well as potentiators that open defective CFTR channels. These therapies are poised to help most individuals with CF, with the notable exception of individuals with class I mutations where full length CFTR protein is not produced. For these mutations, gene replacement has been suggested as a potential solution.In this work, we used a helper dependent adenoviral vector (HD-CFTR) to express CFTR in nasal epithelial cell cultures derived from CF subjects with class I CFTR mutations. CFTR function was significantly restored in CF cells by HD-CFTR and reached healthy control functional levels as detected by Ussing chamber and membrane potential (FLIPR) assay. A dose response relationship was observed between the amount of vector used and subsequent functional outcomes; small amounts of HD-CFTR were sufficient to correct CFTR function. At higher doses, HD-CFTR did not increase CFTR function in healthy control cells above baseline values. This latter observation allowed us to use this vector to benchmark in vitro efficacy testing of CFTR-modulator drugs. In summary, we demonstrate the potential for HD-CFTR to inform in vitro testing and to restore CFTR function to healthy control levels in airway cells with class I or CFTR nonsense mutations.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Cao has nothing to disclose.Conflict of interest: Dr. Ouyang has nothing to disclose.Conflict of interest: Dr. Laselva has nothing to disclose.Conflict of interest: Dr. Bartlett has nothing to disclose.Conflict of interest: Dr. Zhou has nothing to disclose.Conflict of interest: Dr. Duan has nothing to disclose.Conflict of interest: Dr. Gunawardena has nothing to disclose.Conflict of interest: Julie Avolio has nothing to disclose.Conflict of interest: Dr. Bear reports grants from Cystic FIbrosis Canada, grants from CIHR, grants from SickKIds Foundation, during the conduct of the study.Conflict of interest: TG has received consultation fees from Vertex Pharmaceutical Inc.Conflict of interest: Dr. Hu has nothing to disclose.Conflict of interest: Dr. Moraes has nothing to disclose.