title: Pseudotyping the adenovirus serotype 5 capsid with both the fibre and penton of serotype 35 enhances vascular smooth muscle cell transduction.
abstract: Ex vivo gene therapy during coronary artery bypass grafting (CABG) holds great potential to prevent excessive smooth muscle cell (SMC) proliferation, neointima formation and graft failure. The most successful preclinical strategies to date have utilised vectors based on the species C adenovirus, Ad5, which engages the Coxsackie and Adenovirus receptor (CAR) as its primary attachment receptor. Profiling receptors on human SMCs demonstrated the absence of CAR but substantial expression of the species B receptor CD46. We performed transduction experiments using Ad5 and the CD46-utilising adenovirus Ad35, and found Ad35 significantly more efficient at transducing SMCs. To evaluate whether transduction could be further augmented, we evaluated chimeric CD46-utilising Ad5/Ad35 vectors comprising the Ad5 capsid pseudotyped with the Ad35 fibre alone (Ad5/F35) or in combination with the Ad35 penton (Ad5/F35/P35). In human smooth muscle cells (hSMCs), Ad5/F35/P35 mediated significantly higher levels of transduction than either parental vector or Ad5/F35. Ex vivo transduction experiments using mouse aortas from CD46 transgenics demonstrated that Ad5/F35/P35 was significantly more efficient at transducing SMCs than the other vectors tested. Finally, ex vivo transduction and immunofluorescent colocalisation experiments using human tissue from CABG procedures confirmed the preclinical potential of Ad5/F35/P35 as an efficient vector for vascular transduction during CABG.
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Parker
authors.forename: K M
authors.initials: KM
authors.lastname: White
authors.forename: C A
authors.initials: CA
authors.lastname: Lavery
authors.forename: J
authors.initials: J
authors.lastname: Custers
authors.forename: S N
authors.identifier: 0000000349704730
authors.initials: SN
authors.lastname: Waddington
authors.forename: A H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000260:Adenoviruses, Human / Q000145:classification / Q000235:genetics*; D000818:Animals; D001011:Aorta; D002213:Capsid / Q000378:metabolism*; D036022:Capsid Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000150:complications / Q000473:pathology / Q000601:surgery / Q000628:therapy; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism* / Q000821:virology; D058426:Neointima / Q000473:pathology / Q000628:therapy; D014161:Transduction, Genetic
chemical_list: D036022:Capsid Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051916:Membrane Cofactor Protein; C018315:hexon capsid protein, Adenovirus; C043322:penton protein, adenovirus