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Adenovirus 5-fiber 35 chimeric vector mediates efficient apical correction of the CFTR defect in cystic fibrosis primary airway epithelia.

Artikel i vetenskaplig tidskrift
Författare Ophélia Granio
Katherine Ashbourne Excoffon
Petra Henning
Patricia Melin
Caroline Norez
Gaelle Gonzalez
Philip Karp
Maria K Magnusson
Nagy Habib
Leif Lindholm
Frédéric Becq
Pierre Boulanger
Joseph Zabner
Saw See Hong
Publicerad i Human gene therapy
Volym 21
Nummer/häfte 3
Sidor 251-269
ISSN 1557-7422
Publiceringsår 2010
Publicerad vid Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi
Sidor 251-269
Språk en
Länkar dx.doi.org/10.1089/hum.2009.056
Ämneskategorier Mikrobiologi inom det medicinska området

Sammanfattning

In vivo gene transfer to the human respiratory tract using Adenovirus serotype 5 (Ad5) vectors has revealed their limitations related to inefficient gene transfer, host antiviral response and innate adenoviral toxicity. In the present work, we compared the cytotoxicity and efficiency of Ad5 and a chimeric Ad5F35 vector with respect to CFTR gene transfer to cystic fibrosis (CF) and non-CF human airway epithelial cells. We found that high doses of Ad5 vector had an adverse effect on the function of exogenous and endogenous CFTR. Results obtained with Ad5 capsid mutants suggested that the RGD motifs on the penton base capsomers were responsible for the negative effect on the CFTR function. This negative interference was not a result of a lower level of biosynthesis and/or altered cellular trafficking of the CFTR protein, but rather from an indirect mechanism of functional blockage of CFTR, related to the RGD-integrin-mediated endocytic pathway of Ad5. No negative interference with CFTR was observed for Ad5F35, an Ad5-based vector pseudotyped with fibers from Ad35, a serotype which uses another cell entry pathway. In vitro, Ad5F35 vector expressing the GFP-tagged CFTR (Ad5F35-GFP-CFTR) showed a 30-fold higher efficiency of transduction and chloride channel correction in CFTR-deficient cells, compared to Ad5GFP-CFTR. Ex vivo, Ad5F35-GFP-CFTR had the capacity to transduce efficiently reconstituted airway epithelia from CF patients (CF-HAE) via the apical surface, restored the chloride channel function at relatively low vector doses, and showed a relatively stable expression of GFP-CFTR for several weeks.

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