Functional characterization of a recombinant adeno-associated virus 5-pseudotyped cystic fibrosis transmembrane conductance regulator vector

Human Gene Therapy
Jeffrey SirningerTerence R Flotte

Abstract

Despite extensive experience with recombinant adeno-associated virus (rAAV) 2 vectors in the lung, gene expression has been low in the context of cystic fibrosis (CF) gene therapy, where the large size of the cystic fibrosis transmembrane conductance regulator (CFTR) coding sequence has prompted the use of compact endogenous promoter elements. We evaluated the possibility that gene expression from recombinant adeno-associated virus (rAAV) could be improved by using alternate AAV capsid serotypes that target different cell-surface receptors (i.e., rAAV5) and/or using stronger promoters. The relative activities of the cytomegalovirus (CMV) Rous sarcoma virus (RSV) promoter, the CMV enhancer/beta-actin (CB) promoter combination, and the CMV enhancer/RSV promoter hybrid were assessed in vitro in a CF bronchial cell line. The CB promoter was the most efficient. AAV capsid serotypes, rAAV2 and rAAV5, were also compared, and rAAV5 was found to be significantly more efficient. Based on these studies a rAAV5-CB-promoter-driven CFTR minigene vector was then used to correct the CF chloride transport defect in vitro, as well as the hyperinflammatory lung phenotype in Pseudomonas-agarose bead challenged CF mouse lungs in vivo. These studies...Continue Reading

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Citations

Jul 5, 2008·Clinical Reviews in Allergy & Immunology·Christian Mueller, Terence R Flotte
Jan 11, 2012·Protein & Cell·Huibi CaoJim Hu
Jul 16, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Wuping LiR Jude Samulski
Aug 11, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jung Soo SukJustin Hanes
Aug 2, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Xiaoming LiuJohn F Engelhardt
Feb 3, 2011·Proceedings of the National Academy of Sciences of the United States of America·Lynda S OstedgaardMichael J Welsh
Mar 4, 2006·American Journal of Respiratory and Critical Care Medicine·Irina PetracheRubin M Tuder
Oct 1, 2005·American Journal of Respiratory Cell and Molecular Biology·Xiaoming LiuJohn F Engelhardt
Aug 10, 2010·American Journal of Respiratory Cell and Molecular Biology·Ashley T MartinoTerence R Flotte
Jun 20, 2012·Molecular Neurodegeneration·Cheng FangGary Banker
Jun 21, 2014·Biophysics Reviews·Liudmila Cebotaru, William B Guggino
Nov 22, 2005·Expert Opinion on Drug Delivery·Stephen Tate, Stuart Elborn
Feb 20, 2016·Human Gene Therapy Methods·Heather S LoringTerence R Flotte
Jan 14, 2009·Advanced Drug Delivery Reviews·Uta GriesenbachUNKNOWN UK Cystic Fibrosis Gene Therapy Consortium
Mar 15, 2006·Dental Clinics of North America·Christoph A RamseierWilliam V Giannobile
Apr 20, 2005·The Journal of Gene Medicine·Isabel Virella-LowellTerence R Flotte
Sep 28, 2006·The American Journal of Pathology·Irina PetracheRubin M Tuder
Mar 31, 2015·Birth Defects Research. Part C, Embryo Today : Reviews·Kevin NishidaG Ian Gallicano
May 20, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Namho KimJung Soo Suk
Dec 9, 2016·Human Gene Therapy·Dolan SondhiRonald G Crystal
Feb 15, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Anne C FischerWilliam B Guggino
Jan 20, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Terence R FlotteJim Hu
Sep 29, 2011·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·S V MartiniM M Morales
Jun 29, 2017·Expert Opinion on Biological Therapy·William B Guggino, Liudmila Cebotaru
Jan 10, 2020·Human Gene Therapy·Patrizia Tornabene, Ivana Trapani
Aug 18, 2020·Human Gene Therapy·Ana CarneiroDavid V Schaffer
Aug 31, 2020·Human Gene Therapy·William B GugginoLiudmila Cebotaru
Apr 15, 2020·Human Gene Therapy·William B Guggino, Liudmila Cebotaru

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