Abstract
Aerosol gene therapy offers great potential for treating acquired and inherited lung diseases. For treatment of chronic lung diseases such as cystic fibrosis, asthma and emphysema, non-viral gene therapy will likely require repeated administration to maintain transgene expression in slowly dividing, or terminally differentiated, lung epithelial cells. When complexed with plasmid DNA (pDNA), the synthetic polymer, 25 kDa branched Polyethylenimine (PEI), can be formulated for aerosol delivery to the lungs. We show that pDNA/PEI aerosol formulations can be repeatedly administered to airways of mice on at least 10 occasions with no detectable toxicity. Interestingly, peak reporter gene activity upon repeated delivery was significantly reduced by up to 75% compared with a single administration, despite similar pDNA lung deposition at each subsequent aerosol exposure. Although the precise mechanism of inhibition is unknown, it is independent of mouse strain, does not involve an immune response, and is mediated by PEI. Importantly, using a dosing interval of 56 days, delivery of a fourth-generation, CpG-free plasmid generated high-level, sustained transgene expression, which was further boosted at subsequent administrations. Together ...Continue Reading
References
Mar 6, 1992·Cell·P MombaertsV E Papaioannou
Aug 1, 1995·Proceedings of the National Academy of Sciences of the United States of America·O BoussifJ P Behr
Mar 1, 2000·Gene Therapy·R G JenkinsS L Hart
Mar 9, 2000·Journal of Pharmaceutical Sciences·T J Anchordoquy, G S Koe
Aug 2, 2000·Gene Therapy·S C HydeD R Gill
Aug 10, 2000·Molecular Therapy : the Journal of the American Society of Gene Therapy·C L DensmoreV Knight
Aug 10, 2000·Molecular Therapy : the Journal of the American Society of Gene Therapy·N S YewS H Cheng
Dec 29, 2000·Nature·H HemmiS Akira
Apr 21, 2001·Gene Therapy·A GautamJ C Waldrep
Apr 26, 2001·Molecular Therapy : the Journal of the American Society of Gene Therapy·A GautamJ C Waldrep
Jul 5, 2001·The Journal of Gene Medicine·H HerweijerJ A Wolff
Nov 13, 2001·Gene Therapy·D R GillS C Hyde
Feb 6, 2002·The Journal of Gene Medicine·C RudolphJ Rosenecker
Sep 12, 2002·Gene Therapy·A C RoseS C Hyde
Aug 19, 2003·Gene Therapy·J W WisemanW H Colledge
Aug 29, 2003·The Journal of Biological Chemistry·N D SonawaneA S Verkman
Jun 3, 2004·Proceedings of the National Academy of Sciences of the United States of America·Qing GeJianzhu Chen
Aug 4, 2005·Pharmaceutical Research·Lee A DaviesDeborah R Gill
Aug 16, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Carsten RudolphJoseph Rosenecker
Dec 13, 2006·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Petra DamesCarsten Rudolph
Feb 13, 2007·Journal of Controlled Release : Official Journal of the Controlled Release Society·Takayuki IidaTakuro Niidome
Mar 27, 2007·Pharmaceutical Research·Mini ThomasAlexander M Klibanov
Apr 29, 2008·Nature Biotechnology·Stephen C HydeDeborah R Gill
May 20, 2008·American Journal of Physiology. Lung Cellular and Molecular Physiology·Emma L Rawlins, Brigid L M Hogan
May 27, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lee A DaviesDeborah R Gill
Jan 9, 2009·Gene Therapy·D R GillS C Hyde
Dec 8, 2009·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Eugenia LesinaCarsten Rudolph
Sep 22, 2010·BioTechniques·Lee A DaviesDeborah R Gill
Oct 15, 2010·Human Gene Therapy·Christine I WooddellJon A Wolff
Nov 26, 2010·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Melanie GüntherAchim Aigner
Dec 8, 2010·Journal of Aerosol Medicine and Pulmonary Drug Delivery·John S PattonCarsten Ehrhardt
Apr 23, 2011·Gene Therapy·G McLachlanD D S Collie
May 4, 2011·International Journal of Pharmaceutics·Dong ZhaoXun Sun
May 24, 2011·Journal of Controlled Release : Official Journal of the Controlled Release Society·Corinna PfeiferCarsten Rudolph
Aug 23, 2011·Biomaterials·Andrea BeyerleTobias Stoeger
Sep 29, 2011·Biomaterials·Reto P BazzaniDeborah R Gill
Citations
Jul 7, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Ian A PringleStephen C Hyde
Jul 9, 2013·Trends in Biotechnology·Pedro H Oliveira, Juergen Mairhofer
Apr 1, 2014·European Journal of Medicinal Chemistry·Miao-Miao XunXiao-Qi Yu
May 29, 2014·Human Gene Therapy. Clinical Development·Lee A DaviesDeborah R Gill
Aug 7, 2013·Human Molecular Genetics·Uta Griesenbach, Eric W F W Alton
Jan 8, 2013·Expert Opinion on Biological Therapy·Uta Griesenbach, Eric W F W Alton
May 21, 2014·Advanced Drug Delivery Reviews·Ivana d'AngeloFrancesca Ungaro
Jan 20, 2016·Nanomedicine·Jung Soo Suk
Mar 26, 2013·Advanced Healthcare Materials·Zhenhua LiXiaogang Qu
Mar 24, 2016·Biomacromolecules·Ivana d'AngeloFrancesca Ungaro
Jun 4, 2015·Biotechnology Journal·Nawal BelmadiTristan Montier
May 6, 2015·Biomaterials·Mattias F LindbergTristan Montier
Jan 21, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jung Soo SukJustin Hanes
Oct 30, 2014·Frontiers in Molecular Neuroscience·Mary-Louise RogersNicolas H Voelcker
Apr 30, 2014·Human Gene Therapy. Clinical Development·Lee Adrian DaviesDeborah Rebecca Gill
May 20, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Namho KimJung Soo Suk
Jul 19, 2016·Expert Opinion on Drug Delivery·Larissa Gomes Dos ReisDaniela Traini
Jul 28, 2016·The Journal of Gene Medicine·Lyudmila S KrassikovaAlexander V Belyavsky
Nov 6, 2015·International Journal of Molecular Sciences·Nawal BelmadiTristan Montier
Mar 3, 2018·Cancers·Urska KamensekMaja Cemazar
Dec 6, 2018·Biotechnology & Genetic Engineering Reviews·Suleiman Yusuf AlhajiSyahril Abdullah
Jul 25, 2019·Journal of Clinical Medicine·Laura M TrandafirElena Cojocaru
Oct 20, 2017·Bioscience Reports·Angélique MottaisTristan Montier
Sep 2, 2017·Scientific Reports·Jean-François GélinasStephen C Hyde
Dec 22, 2020·PloS One·Omar HabibSyahril Abdullah
May 18, 2020·Advanced Drug Delivery Reviews·Tao Wan, Yuan Ping
Jul 10, 2019·International Journal of Pharmaceutics·Angélique MottaisTristan Montier
Apr 12, 2016·Biomaterials·Reto P BazzaniDeborah R Gill