title: Ex vivo adenoviral vector gene delivery results in decreased vector-associated inflammation pre- and post-lung transplantation in the pig.
abstract: Acellular normothermic ex vivo lung perfusion (EVLP) is a novel method of donor lung preservation for transplantation. As cellular metabolism is preserved during perfusion, it represents a potential platform for effective gene transduction in donor lungs. We hypothesized that vector-associated inflammation would be reduced during ex vivo delivery due to isolation from the host immune system response. We compared ex vivo with in vivo intratracheal delivery of an E1-, E3-deleted adenoviral vector encoding either green fluorescent protein (GFP) or interleukin-10 (IL-10) to porcine lungs. Twelve hours after delivery, the lung was transplanted and the post-transplant function assessed. We identified significant transgene expression by 12 hours in both in vivo and ex vivo delivered groups. Lung function remained excellent in all ex vivo groups after viral vector delivery; however, as expected, lung function decreased in the in vivo delivered adenovirus vector encoding GFP (AdGFP) group with corresponding increases in IL-1β levels. Transplanted lung function was excellent in the ex vivo transduced lungs and inferior lung function was seen in the in vivo group after transplantation. In summary, ex vivo delivery of adenoviral gene therapy to the donor lung is superior to in vivo delivery in that it leads to less vector-associated inflammation and provides superior post-transplant lung function.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Yeung
authors.forename: Dirk
authors.initials: D
authors.lastname: Wagnetz
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cypel
authors.forename: Matthew
authors.initials: M
authors.lastname: Rubacha
authors.forename: Terumoto
authors.initials: T
authors.lastname: Koike
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Chun
authors.forename: Jim
authors.initials: J
authors.lastname: Hu
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: David M
authors.initials: DM
authors.lastname: Hwang
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000502:physiology; D016040:Lung Transplantation / Q000276:immunology*; D008297:Male; D010477:Perfusion; D011014:Pneumonia / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D013552:Swine; D019076:Transgenes
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators